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Boonpeng A, Singkham N, Wutthikul C, Rattanakul T, Weeket P, Saengpraphanan C, Plaengnok R. Population Pharmacokinetic Simulations for Dose Optimization of Tenofovir Disoproxil Fumarate in HIV-Infected Patients with Moderate-to-Severe Renal Impairment. J Clin Pharmacol 2025; 65:424-432. [PMID: 39415758 DOI: 10.1002/jcph.6153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Accepted: 09/30/2024] [Indexed: 10/19/2024]
Abstract
Tenofovir disoproxil fumarate (TDF) requires dosage adjustments from the standard 300 mg once daily to every 48-96 h for moderate-to-severe renal impairment to avoid excessive exposure. However, this extended interval can lead to variable drug exposure and inconvenience. This study aimed to utilize the population pharmacokinetic (PPK) models to optimize TDF dosing regimens for HIV-infected patients with renal impairment. A systematic literature search was conducted across PubMed, Cochrane Library, and Scopus databases to identify relevant PPK studies of TDF in HIV-infected patients. From the included studies, the PPK models and associated parameters were extracted. Monte Carlo simulations (n = 2000) were performed to generate concentration-time profiles and derive PK parameters compared against reference ranges. For moderate renal impairment, the TDF 150 mg once-daily regimen achieved cumulative exposure comparable to the approved 300 mg every-other-day regimen. In severe renal impairment, TDF 75-100 mg administered once daily provided similar cumulative exposure as 300 mg every 72-96 h regimen while maintaining daily exposure comparable to the standard dose in patients with normal renal function. The approved extended dosing intervals of 72-96 h exhibited high drug exposure variability, initially resulting in supratherapeutic levels followed by suboptimal levels preceding the subsequent dose administration. In conclusion, administering smaller once-daily doses of TDF maintains consistent daily drug exposure comparable to the standard dose in patients with normal renal function while reducing variability in drug exposure, potentially mitigating the risk of nephrotoxicity. However, additional clinical studies are required to confirm these findings.
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Affiliation(s)
- Apinya Boonpeng
- School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand
| | - Noppaket Singkham
- School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand
- Unit of Excellence on Pharmacogenomic Pharmacokinetic and Pharmacotherapeutic Researches (UPPER), School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand
| | - Chanadda Wutthikul
- School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand
| | | | - Pinmanee Weeket
- School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand
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Tajiri K, Hayashi Y, Murayama A, Muraishi N, Minemura M, Yasuda I. Decrease in HBsAg After TAF Switching from Entecavir During Long-Term Treatment of Chronic Hepatitis B Virus Infection. Viruses 2024; 17:44. [PMID: 39861833 PMCID: PMC11769490 DOI: 10.3390/v17010044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Revised: 12/25/2024] [Accepted: 12/30/2024] [Indexed: 01/30/2025] Open
Abstract
Achieving HBsAg seroclearance is a key goal in treating chronic hepatitis B virus (HBV) infection but remains difficult with nucleos(t)ide analogues (NAs). Tenofovir alafenamide fumarate (TAF), a recommended NA for managing chronic HBV infection (CHB), has uncertain effects on HBsAg levels and potential adverse events when used long-term after switching from entecavir (ETV). We retrospectively evaluated 77 CHB patients, including 47 who switched from ETV to TAF with a median follow-up of 40 months post-switch and a median of 60 months of HBsAg monitoring pre-switch. No significant change in HBsAg levels was observed in the overall cohort post-switch, consistent with the ETV continuation group. However, a significant decrease in HBsAg was noted in patients with HBsAg < 100 IU/mL at the time of switching. HBsAg loss occurred in three patients who switched to TAF. No adverse effects were observed, and TAF was well tolerated. The most significant factor associated with achieving HBsAg < 100 IU/mL was the Fib-4 index, a marker of liver fibrosis, at the time of switching. Switching from ETV to TAF is an effective strategy in CHB management, with hepatic inflammation potentially playing an essential role in achieving HBsAg decrease. Patients with increased Fib-4 index were significantly more likely to show decreased HBsAg. This finding suggests patients with mild to moderate fibrosis may respond better to TAF in terms of HBsAg reduction.
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Affiliation(s)
- Kazuto Tajiri
- Third Department of Internal Medicine, Faculty of Medicine, Academic Assembly, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan; (Y.H.); (A.M.); (N.M.); (M.M.); (I.Y.)
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Gouissi Anguechia DH, Bouba Y, Semengue ENJ, Ka’e AC, Takou D, Ambe Chenwi C, Beloumou G, Nka AD, Basseck Wome UR, Santoro MM, Ceccherini-Silberstein F, Chatté A, Montesano C, Cappelli G, Colizzi V, Ndjolo A, Mbanya D, Ndembi N, Perno CF, Fokam J. Predictive Efficacy of Dual Therapies Combining Integrase Strand Transfer Inhibitors with Second-Generation Non-Nucleoside Reverse Transcriptase Inhibitors Following HIV-1 Treatment Failure in Cameroon: Implications for the Use of a Long-Acting Therapeutic Strategy in Low- and Middle-Income Countries. Viruses 2024; 16:1853. [PMID: 39772163 PMCID: PMC11680099 DOI: 10.3390/v16121853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 11/09/2024] [Accepted: 11/14/2024] [Indexed: 01/30/2025] Open
Abstract
Dual therapies (DT) combining integrase strand transfer inhibitors (INSTIs) with second-generation non-nucleoside reverse transcriptase inhibitors (2nd-Gen-NNRTIs) offer new possibilities for HIV treatment to improve adherence. However, drug resistance associated mutations (RAMs) to prior antiretrovirals may jeopardize the efficacy of DT. We herein describe the predicted efficacy of DT combining INSTIs + 2nd-Gen-NNRTI following treatment failure among Cameroonian patients. We genotyped the HIV-1 pol gene using Sanger sequencing and assessed acquired RAMs to NNRTIs and INSTIs in patients failing treatment from March 2019 to December 2023. Drug susceptibility was interpreted using Stanford HIVdb v9.5, and statistical analyses were performed using SPSS v22. Of 130 successfully genotyped participants (median age (IQR): 38 (27-46) years; 59.2% female), 92.3% had RAMs to NNRTIs and 1.5% to INSTIs. Prevailing RAMs were Y181C (32.3%) among NNRTIs and R263K (0.7%) among INSTIs. Among 2nd-Gen-NNRTIs, etravirine, doravirine and rilpivirine had 43.85%, 41.54% and 38.46% genotypic sensitivity, respectively. Among INSTIs, we found 97.69% efficacy for dolutegravir/bictegravir, 96.15% for cabotegravir and 92.31% for elvitegravir/raltegravir. The overall predictive efficacy of DT was lower among participants who failed 1st-Gen-NNRTI (p < 0.001); with etravirine + dolutegravir/bictegravir combination showing the highest score (43.8%). Conclusively, DT combining INSTIs + 2nd-Gen-NNRTIs might be suboptimal in the context of previous ART failure, especially with NNRTI-based treatment in low- and middle-income countries. The general data clearly indicate that without resistance testing, it is nearly impossible to use long-acting dual therapies in previously failing patients.
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Affiliation(s)
- Davy-Hyacinthe Gouissi Anguechia
- Chantal BIYA International Reference Centre for Research on HIV/AIDS Prevention and Management, Yaoundé P.O. Box 3077, Cameroon; (D.-H.G.A.); (Y.B.); (E.N.J.S.); (A.C.K.); (D.T.); (C.A.C.); (G.B.); (A.D.N.); (U.R.B.W.); (V.C.); (A.N.); (C.-F.P.)
- Faculty of Medicine and Biomedical Sciences, University of Yaoundé I, Yaoundé P.O. Box 337, Cameroon;
| | - Yagai Bouba
- Chantal BIYA International Reference Centre for Research on HIV/AIDS Prevention and Management, Yaoundé P.O. Box 3077, Cameroon; (D.-H.G.A.); (Y.B.); (E.N.J.S.); (A.C.K.); (D.T.); (C.A.C.); (G.B.); (A.D.N.); (U.R.B.W.); (V.C.); (A.N.); (C.-F.P.)
- Faculty of Medicine, UniCamillus-Saint Camillus International University of Health Sciences, 00131 Rome, Italy
| | - Ezechiel Ngoufack Jagni Semengue
- Chantal BIYA International Reference Centre for Research on HIV/AIDS Prevention and Management, Yaoundé P.O. Box 3077, Cameroon; (D.-H.G.A.); (Y.B.); (E.N.J.S.); (A.C.K.); (D.T.); (C.A.C.); (G.B.); (A.D.N.); (U.R.B.W.); (V.C.); (A.N.); (C.-F.P.)
- National HIV Drug Resistance Working Group, Yaoundé P.O. Box 1459, Cameroon
| | - Aude Christelle Ka’e
- Chantal BIYA International Reference Centre for Research on HIV/AIDS Prevention and Management, Yaoundé P.O. Box 3077, Cameroon; (D.-H.G.A.); (Y.B.); (E.N.J.S.); (A.C.K.); (D.T.); (C.A.C.); (G.B.); (A.D.N.); (U.R.B.W.); (V.C.); (A.N.); (C.-F.P.)
| | - Désiré Takou
- Chantal BIYA International Reference Centre for Research on HIV/AIDS Prevention and Management, Yaoundé P.O. Box 3077, Cameroon; (D.-H.G.A.); (Y.B.); (E.N.J.S.); (A.C.K.); (D.T.); (C.A.C.); (G.B.); (A.D.N.); (U.R.B.W.); (V.C.); (A.N.); (C.-F.P.)
- National HIV Drug Resistance Working Group, Yaoundé P.O. Box 1459, Cameroon
| | - Collins Ambe Chenwi
- Chantal BIYA International Reference Centre for Research on HIV/AIDS Prevention and Management, Yaoundé P.O. Box 3077, Cameroon; (D.-H.G.A.); (Y.B.); (E.N.J.S.); (A.C.K.); (D.T.); (C.A.C.); (G.B.); (A.D.N.); (U.R.B.W.); (V.C.); (A.N.); (C.-F.P.)
- National HIV Drug Resistance Working Group, Yaoundé P.O. Box 1459, Cameroon
- Department of Experimental Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy; (M.M.S.); (F.C.-S.)
| | - Grace Beloumou
- Chantal BIYA International Reference Centre for Research on HIV/AIDS Prevention and Management, Yaoundé P.O. Box 3077, Cameroon; (D.-H.G.A.); (Y.B.); (E.N.J.S.); (A.C.K.); (D.T.); (C.A.C.); (G.B.); (A.D.N.); (U.R.B.W.); (V.C.); (A.N.); (C.-F.P.)
| | - Alex Durand Nka
- Chantal BIYA International Reference Centre for Research on HIV/AIDS Prevention and Management, Yaoundé P.O. Box 3077, Cameroon; (D.-H.G.A.); (Y.B.); (E.N.J.S.); (A.C.K.); (D.T.); (C.A.C.); (G.B.); (A.D.N.); (U.R.B.W.); (V.C.); (A.N.); (C.-F.P.)
| | - Ulrich Roland Basseck Wome
- Chantal BIYA International Reference Centre for Research on HIV/AIDS Prevention and Management, Yaoundé P.O. Box 3077, Cameroon; (D.-H.G.A.); (Y.B.); (E.N.J.S.); (A.C.K.); (D.T.); (C.A.C.); (G.B.); (A.D.N.); (U.R.B.W.); (V.C.); (A.N.); (C.-F.P.)
| | - Maria Mercedes Santoro
- Department of Experimental Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy; (M.M.S.); (F.C.-S.)
| | | | - Adawaye Chatté
- Project Management Unit, Ministry of Health, N’djamena P.O. Box 548, Chad;
| | - Carla Montesano
- Department of Biology, University of Rome “Tor Vergata”, 00133 Rome, Italy;
| | - Giulia Cappelli
- National Research Council, 00185 Rome, Italy;
- LAGET, Centre Hospitalo-Universitaire (CHU), N’djamena P.O. Box 456, Chad
| | - Vittorio Colizzi
- Chantal BIYA International Reference Centre for Research on HIV/AIDS Prevention and Management, Yaoundé P.O. Box 3077, Cameroon; (D.-H.G.A.); (Y.B.); (E.N.J.S.); (A.C.K.); (D.T.); (C.A.C.); (G.B.); (A.D.N.); (U.R.B.W.); (V.C.); (A.N.); (C.-F.P.)
- LAGET, Centre Hospitalo-Universitaire (CHU), N’djamena P.O. Box 456, Chad
- EUROBIOPARK and UNSECO Board for Biotechnology, University of Rome “Tor Vergata”, 00133 Rome, Italy
- Faculty of Sciences and Technology, Evangelical University of Cameroon, Bandjoun P.O. Box 127, Cameroon
| | - Alexis Ndjolo
- Chantal BIYA International Reference Centre for Research on HIV/AIDS Prevention and Management, Yaoundé P.O. Box 3077, Cameroon; (D.-H.G.A.); (Y.B.); (E.N.J.S.); (A.C.K.); (D.T.); (C.A.C.); (G.B.); (A.D.N.); (U.R.B.W.); (V.C.); (A.N.); (C.-F.P.)
- Faculty of Medicine and Biomedical Sciences, University of Yaoundé I, Yaoundé P.O. Box 337, Cameroon;
| | - Dora Mbanya
- Faculty of Medicine and Biomedical Sciences, University of Yaoundé I, Yaoundé P.O. Box 337, Cameroon;
| | - Nicaise Ndembi
- Africa Centres for Disease Control and Prevention, Addis Ababa P.O. Box 3243, Ethiopia
- Institute of Human Virology, Baltimore, MD 21201, USA
| | - Carlo-Federico Perno
- Chantal BIYA International Reference Centre for Research on HIV/AIDS Prevention and Management, Yaoundé P.O. Box 3077, Cameroon; (D.-H.G.A.); (Y.B.); (E.N.J.S.); (A.C.K.); (D.T.); (C.A.C.); (G.B.); (A.D.N.); (U.R.B.W.); (V.C.); (A.N.); (C.-F.P.)
- Bambino Gesù Children Hospital, IRCCS, 00146 Rome, Italy
| | - Joseph Fokam
- Chantal BIYA International Reference Centre for Research on HIV/AIDS Prevention and Management, Yaoundé P.O. Box 3077, Cameroon; (D.-H.G.A.); (Y.B.); (E.N.J.S.); (A.C.K.); (D.T.); (C.A.C.); (G.B.); (A.D.N.); (U.R.B.W.); (V.C.); (A.N.); (C.-F.P.)
- National HIV Drug Resistance Working Group, Yaoundé P.O. Box 1459, Cameroon
- Faculty of Health Sciences, University of Buea, Buea P.O. Box 63, Cameroon
- Central Technical Group, National AIDS Control Committee, Yaoundé P.O. Box 1459, Cameroon
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Ellis RJ, Pal S, Achim CL, Sundermann E, Moore DJ, Soontornniyomkij V, Feldman H. Alzheimer-Type Cerebral Amyloidosis in the Context of HIV Infection: Implications for a Proposed New Treatment Approach. J Neuroimmune Pharmacol 2024; 19:27. [PMID: 38829507 PMCID: PMC11147830 DOI: 10.1007/s11481-024-10126-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Accepted: 05/13/2024] [Indexed: 06/05/2024]
Abstract
Reverse transcriptase inhibitors (RTIs) are currently broadly prescribed for the treatment of HIV infection but are also thought to prevent Alzheimer's disease (AD) progression by protecting against amyloidosis. Our study evaluates the hypothesis that reverse transcriptase inhibitors protect against Alzheimer-type brain amyloidogenesis in the context of HIV infection. We compiled a case series of participants from a prospective study of the neurological consequences of HIV infection at the HIV Neurobehavioral Research Program (HNRP) who had serial neuropsychological and neurological assessments and were on RTIs. Two participants had gross and microscopic examination and immunohistochemistry of the brain at autopsy; one was assessed clinically for Alzheimer's disease by cerebrospinal fluid (CSF) analysis of phosphorylated-Tau, Total-Tau and Aβ42. Additionally, a larger cohort of 250 autopsied individuals was evaluated for presence of amyloid plaques, Tau, and related pathologies. Three older, virally suppressed individuals with HIV who had long-term treatment with RTIs were included in analyses. Two cases demonstrated substantial cerebral amyloid deposition at autopsy. The third case met clinical criteria for AD based on a typical clinical course and CSF biomarker profile. In the larger cohort of autopsied individuals, the prevalence of cerebral amyloidosis among people with HIV (PWH) was greater for those on RTIs. Our study showed that long-term RTI therapy did not protect against Alzheimer-type brain amyloidogenesis in the context of HIV infection in these patients. Given the known toxicities of RTIs, it is premature to recommend them to individuals at risk or with Alzheimer's disease who do not have HIV infection.
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Affiliation(s)
- Ronald J Ellis
- Department of Neuroscience, University of California, San Diego, CA, USA.
- Department of Psychiatry, University of California, San Diego, CA, USA.
| | - Shibangi Pal
- Department of Psychiatry, University of California, San Diego, CA, USA
| | - Cristian L Achim
- Department of Psychiatry, University of California, San Diego, CA, USA
| | - Erin Sundermann
- Department of Psychiatry, University of California, San Diego, CA, USA
| | - David J Moore
- Department of Psychiatry, University of California, San Diego, CA, USA
| | | | - Howard Feldman
- Department of Neuroscience, University of California, San Diego, CA, USA
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Ellis RJ, Marquine MJ, Kaul M, Fields JA, Schlachetzki JCM. Mechanisms underlying HIV-associated cognitive impairment and emerging therapies for its management. Nat Rev Neurol 2023; 19:668-687. [PMID: 37816937 PMCID: PMC11052664 DOI: 10.1038/s41582-023-00879-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/07/2023] [Indexed: 10/12/2023]
Abstract
People living with HIV are affected by the chronic consequences of neurocognitive impairment (NCI) despite antiretroviral therapies that suppress viral replication, improve health and extend life. Furthermore, viral suppression does not eliminate the virus, and remaining infected cells may continue to produce viral proteins that trigger neurodegeneration. Comorbidities such as diabetes mellitus are likely to contribute substantially to CNS injury in people living with HIV, and some components of antiretroviral therapy exert undesirable side effects on the nervous system. No treatment for HIV-associated NCI has been approved by the European Medicines Agency or the US Food and Drug Administration. Historically, roadblocks to developing effective treatments have included a limited understanding of the pathophysiology of HIV-associated NCI and heterogeneity in its clinical manifestations. This heterogeneity might reflect multiple underlying causes that differ among individuals, rather than a single unifying neuropathogenesis. Despite these complexities, accelerating discoveries in HIV neuropathogenesis are yielding potentially druggable targets, including excessive immune activation, metabolic alterations culminating in mitochondrial dysfunction, dysregulation of metal ion homeostasis and lysosomal function, and microbiome alterations. In addition to drug treatments, we also highlight the importance of non-pharmacological interventions. By revisiting mechanisms implicated in NCI and potential interventions addressing these mechanisms, we hope to supply reasons for optimism in people living with HIV affected by NCI and their care providers.
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Affiliation(s)
- Ronald J Ellis
- Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
- Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
| | - María J Marquine
- Department of Medicine, Duke University, Durham, NC, USA
- Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA
| | - Marcus Kaul
- School of Medicine, Division of Biomedical Sciences, University of California Riverside, Riverside, CA, USA
| | - Jerel Adam Fields
- Department of Psychiatry, University of California San Diego, La Jolla, CA, USA
| | - Johannes C M Schlachetzki
- Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA
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Jiang SX, Duncan J, Ko HH. Acquired Fanconi Syndrome from Tenofovir Treatment in a Patient with Hepatitis B. Case Reports Hepatol 2023; 2023:6158407. [PMID: 37362623 PMCID: PMC10290559 DOI: 10.1155/2023/6158407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 12/03/2021] [Accepted: 12/04/2021] [Indexed: 06/28/2023] Open
Abstract
Fanconi syndrome is a rare disease of generalized proximal tubule dysfunction which can be acquired secondary to certain medications, including tenofovir, a commonly used hepatitis B treatment. Signs and symptoms of ensuing renal wasting can be severe but vague, leading to potentially avoidable invasive investigations and delays in diagnosis. We present a case of a 62-year-old female with chronic hepatitis B on tenofovir treatment who was found to have subacute weakness, anorexia, and weight loss. She underwent extensive investigations including computed tomography (CT) imaging, bronchoscopy, upper and lower endoscopy, and psychiatric evaluation. Finally, persistent electrolyte derangements led to urine studies, which demonstrated acquired Fanconi syndrome secondary to tenofovir. After discontinuing tenofovir disoproxil fumarate and starting tenofovir alafenamide, her symptoms resolved and her renal function recovered. This case illustrates the importance of maintaining clinical suspicion for tenofovir-induced Fanconi syndrome, given the common use of tenofovir as first-line hepatitis B treatment and the availability of less nephrotoxic alternatives.
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Affiliation(s)
- Shirley X. Jiang
- Department of Medicine, University of British Columbia, Vancouver, Canada
| | - John Duncan
- Division of Nephrology, Faculty of Medicine, University of British Columbia, Vancouver, Canada
| | - Hin Hin Ko
- Division of Gastroenterology, Faculty of Medicine, University of British Columbia, Vancouver, Canada
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Ellis RJ, Pal S, Achim CL, Sundermann E, Moore DJ, Soontornniyomkij V, Feldman H. Alzheimer-type cerebral amyloidosis in the context of HIV infection: implications for a proposed new treatment approach. RESEARCH SQUARE 2023:rs.3.rs-3040756. [PMID: 37398361 PMCID: PMC10312930 DOI: 10.21203/rs.3.rs-3040756/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/04/2023]
Abstract
Reverse transcriptase inhibitors (RTIs) are currently broadly prescribed for the treatment of HIV infection but are also thought to prevent Alzheimer's Disease (AD) progression by protecting against amyloidosis. Our study evaluates the hypothesis that reverse transcriptase inhibitors protect against Alzheimer-type brain amyloidogenesis in the context of HIV infection. We compiled a case series of participants from a prospective study of the neurological consequences of HIV infection at the HIV Neurobehavioral Research Program (HNRP) who had serial neuropsychological and neurological assessments and were on RTIs. Two participants had gross and microscopic examination and immunohistochemistry of the brain at autopsy; one was assessed clinically for Alzheimer's Disease by cerebrospinal fluid (CSF) analysis of phosphorylated-Tau, Total-Tau and Aβ42. Additionally, a larger cohort of autopsied individuals was evaluated for presence of amyloid plaques, Tau, and related pathologies. Three older, virally suppressed individuals with HIV who had long-term treatment with RTIs were included in analyses. Two cases demonstrated substantial cerebral amyloid deposition at autopsy. The third case met clinical criteria for AD based on a typical clinical course and CSF biomarker profile. In the larger cohort of autopsied individuals, the prevalence of cerebral amyloidosis among people with HIV (PWH) was greater for those on RTIs. Our study showed that long-term RTI therapy did not protect against Alzheimer-type brain amyloidogenesis in the context of HIV infection in these patients. Given the known toxicities of RTIs, it is premature to recommend them to individuals at risk or with Alzheimer's disease who do not have HIV infection.
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Zilwa N, Mpejane O, Mehboob G, Gill S, Kalinoski T. Fanconi syndrome, diabetes insipidus, and acute kidney injury due to tenofovir disoproxil fumarate: A case report. Antivir Ther 2023; 28:13596535231186727. [PMID: 37368845 DOI: 10.1177/13596535231186727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/29/2023]
Abstract
BACKGROUND Tenofovir disoproxil fumarate is widely used in Botswana as part of the first-line antiretroviral regimen in the 'Treat All' strategy implemented in 2016 by the Ministry of Health. Its use has been associated with several uncommon adverse renal effects, though rarely all in conjunction or without the combined use of protease inhibitors. CASE PRESENTATION A 49-year-old woman living with HIV whose viral load is suppressed on tenofovir disoproxil fumarate, lamivudine, and dolutegravir presented with 1 day of generalized weakness and myalgia causing an inability to ambulate. This was associated with nausea and vomiting and profound fatigue. She was found to have an acute kidney injury, non-anion-gap metabolic acidosis, hypernatremia, hypokalemia, and hypophosphatemia. Urinalysis revealed pyuria with white blood cell casts, glucosuria, and proteinuria. The diagnosis was made of tenofovir-induced nephrotoxicity. The tenofovir was discontinued, and the patient was initiated on intravenous fluids and electrolyte and bicarbonate supplementation with improvement in her symptoms and laboratory values. CONCLUSIONS This report suggests the possibility of severe tenofovir-induced nephrotoxicity with combined acute kidney injury, Fanconi syndrome, and nephrogenic diabetes insipidus in the absence of other provoking factors such as use with protease inhibitors or advanced HIV disease, chronic kidney disease, and age. With its wide use in Botswana and other countries, health-care providers should have a high index of suspicion for tenofovir-induced nephrotoxicity for HIV patients on tenofovir with deranged renal function tests and electrolytes.
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Affiliation(s)
| | | | - Golam Mehboob
- Department of Medicine, Scottish Livingstone Hospital, Molepolole, Botswana
| | - Sajan Gill
- Department of Medicine, Oregon Health & Science University, Portland, OR, USA
| | - Thomas Kalinoski
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
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Gizaw A, King WC, Hinerman AS, Chung RT, Lisker-Melman M, Ghany MG, Khalili M, Jain MK, Graham J, Swift-Scanlan T, Kleiner DE, Sulkowski M, Wong DK, Sterling RK. A prospective cohort study of renal function and bone turnover in adults with hepatitis B virus (HBV)-HIV co-infection with high prevalence of tenofovir-based antiretroviral therapy use. HIV Med 2023; 24:55-74. [PMID: 35578388 PMCID: PMC9666620 DOI: 10.1111/hiv.13322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Accepted: 04/17/2022] [Indexed: 01/22/2023]
Abstract
OBJECTIVE Tenofovir disoproxil fumarate (TDF) is a common component of antiretroviral therapy in hepatitis B virus (HBV)-HIV co-infected adults but few studies have evaluated worsening renal function and bone turnover, known effects of TDF. METHODS Adults from eight North American sites were enrolled in this cohort study. Research assessments were conducted at entry and every 24 weeks for ≤192 weeks. Bone markers were tested at baseline, week 96 and week 192 from stored serum. We evaluated changes in markers of renal function and bone turnover over time and potential contributing factors. RESULTS A total of 115 patients were prospectively followed; median age 49 years, 91% male and 52% non-Hispanic Black. Duration of HIV was 20.5 years. TDF use ranged from 80% to 92% throughout follow-up. Estimated glomerular filtration rate (eGFR) (ml/min/1.73m2 ) decreased from 87.1 to 79.9 over 192 weeks (p < 0.001); however, the prevalence of eGFR <60 ml/min/1.73m2 did not appear to differ over time (always <16%; p = 0.43). From baseline to week 192, procollagen type I N-terminal propeptide (P1NP) (146.7 to 130.5 ng/ml; p = 0.001), osteocalcin (14.4 to 10.2 ng/ml; p < 0.001) and C-terminal telopeptides of type I collagen (CTX-1) (373 to 273 pg/ml; p < 0.001) decreased. Younger age, male sex and overweight/obesity versus normal weight predicted a decrease in eGRF. Black race, healthy weight versus underweight, advanced fibrosis, undetectable HBV DNA, and lower parathyroid hormone level predicted worsening bone turnover. CONCLUSION In this HBV-HIV cohort with high prevalence of TDF use, several biomarkers of renal function and bone turnover indicated worsening status over approximately 4 years, highlighting the importance of clinical awareness in co-infected adults.
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Affiliation(s)
- Andinet Gizaw
- Virginia Commonwealth University, Richmond, Virginia, USA
| | - Wendy C. King
- University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, USA
| | - Amanda S. Hinerman
- University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, USA
| | - Raymond T. Chung
- Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Mauricio Lisker-Melman
- Washington University School of Medicine and John Cochran VA Medical Center, St. Louis, Missouri, USA
| | - Marc G. Ghany
- National Institute of Health, Bethesda, Maryland, USA
| | - Mandana Khalili
- University of California San Francisco, San Francisco, California, USA
| | - Mamta K. Jain
- University of Texas Southwestern and Parkland Health & Hospital System, Dallas, Texas, USA
| | - Jacob Graham
- Biobehavioral Research Lab, Virginia Commonwealth University School of Nursing
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10
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Phuphuakrat A, Pasomsub E, Chantratita W, Mahasirimongkol S, Disthabanchong S, Sungkanuparph S, Kiertiburanakul S. Risk Factors of Renal Tubular Dysfunction in Thai People Living with HIV Receiving Tenofovir Disoproxil Fumarate. J Int Assoc Provid AIDS Care 2022; 21:23259582221134751. [PMID: 36314476 PMCID: PMC9623366 DOI: 10.1177/23259582221134751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Tenofovir disoproxil fumarate (TDF) associates with renal tubular dysfunction (RTD) in some people living with HIV (PLWH). We studied clinical and genetic factors associated with RTD in Thai PLWH receiving TDF. RTD was diagnosed in 13 of 65 (20%) patients. The median (interquartile range) age and CD4 cell counts were 43.8 (40.4-50.9) years and 554 (437-716) cells/mm3, respectively. The median duration of TDF use was 46.9 (31.5-54.1) months. Univariate logistic regression demonstrated body mass index (BMI), concomitant use of protease inhibitor (PI), hyperlipidemia, and homozygous C/C SNP rs1059751 of ABCC4 gene as predisposing factors of RTD. In multivariate model, concomitant use of PI [adjusted odds ratio (aOR) 11.39; 95% confidence interval (CI), 1.59- 81.56; P = 0.015], hyperlipidemia (aOR 8.59; 95% CI, 1.46-50.40; P = 0.017), and BMI (aOR 0.76; 95% CI, 0.59-0.98; P = 0.037) remained associated with RTD in patients receiving TDF. PLWH receiving TDF with the presence of these factors should be closely monitored for RTD.
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Affiliation(s)
- Angsana Phuphuakrat
- Department of Medicine, Faculty of Medicine Ramathibodi Hospital,
Bangkok, Thailand,Sasisopin Kiertiburanakul, Division of
Infectious Diseases, Department of Medicine, Faculty of Medicine Ramathibodi
Hospital, Mahidol University, Bangkok, 10400, Thailand.
| | - Ekawat Pasomsub
- Department of Pathology, Faculty of Medicine Ramathibodi Hospital,
Bangkok, Thailand
| | - Wasun Chantratita
- Center for Medical Genomics, Faculty of Medicine Ramathibodi
Hospital, Mahidol University, Bangkok, Thailand
| | - Surakameth Mahasirimongkol
- Division of Genomic Medicine and Innovation Support, Department of
Medical Sciences, Ministry of Public Health, Nonthaburi, Thailand
| | - Sinee Disthabanchong
- Department of Medicine, Faculty of Medicine Ramathibodi Hospital,
Bangkok, Thailand
| | - Somnuek Sungkanuparph
- Chakri Naruebodindra Medical Institute, Faculty of Medicine
Ramathibodi Hospital, Mahidol University, Samut Prakan, Thailand
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11
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Karoney MJ, Koech MK, Njiru EW, Owino Ong’or WD. Proximal tubular renal dysfunction among HIV infected patients on Tenofovir versus Tenofovir sparing regimen in western Kenya. PLoS One 2022; 17:e0273183. [PMID: 36108078 PMCID: PMC9477312 DOI: 10.1371/journal.pone.0273183] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Accepted: 08/03/2022] [Indexed: 11/18/2022] Open
Abstract
INTRODUCTION Tenofovir Disoproxil Fumarate (TDF) is the most widely used Anti-Retroviral Therapy (ART) drug due to its potency, safety profile and World Health Organization (WHO) recommendation. TDF causes proximal tubular renal dysfunction (PTRD) leading to Fanconi syndrome, acute kidney injury and chronic kidney disease. Modest rates (2-4%) of TDF related toxicity based on estimated Glomerular Filtration Rate (GFR) have been described, while TDF-induced PTRD has been reported to be 22%. TDF toxicity is more likely among African patients, it is reversible and TDF may be renal dosed in patients with dysfunction. The objective of this study was to assess proximal tubular renal dysfunction, global renal function, and their determinants among patients on TDF versus TDF-sparing regimen. METHODS This was a cross-sectional study among people living with HIV/AIDS (PLWHA) attending the Academic Model Providing Access to Healthcare (AMPATH) program. The primary outcome of interest in this study was PTRD while the secondary outcome of interest was estimated GFR. PTRD was defined as any two of beta-2 microglobulin in urine, metabolic acidosis, normoglycemic glucosuria and fractional excretion of phosphate. Student's t-test, chi-square and their non-parametric equivalents were used to test for statistical significance. Univariate and multivariate logistic regression analysis was carried out. RESULTS A total of 516 participants were included in the final analysis, 261 on TDF while 255 were on TDF-sparing regimens. The mean (SD) age of all participants was 41.5 (12.6) years with majority being female (60.3%). The proportion of PTRD was 10.0% versus 3.1% in the TDF compared to TDF-sparing group (P<0.001). Mean estimated GFR was 112.8 (21.5) vs 109.7 (21.9) ml/min/1.73mm3 (P = 0.20) for the TDF compared to TDF-sparing group. TDF users were more likely to have PTRD compared to non-TDF users, adjusted Odds Ratio (AOR) 3.0, 95% CI 1.12 to 7.75. CONCLUSION There was significant PTRD in the TDF compared to TDF-sparing group without significant difference in estimated GFR. The clinical significance of these findings may not be clear in the short term.
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Affiliation(s)
- Mercy Jelagat Karoney
- Department of Medicine, College of Health Sciences, School of Medicine, Moi University, Eldoret, Kenya
| | - Mathew Kirtptonui Koech
- Department of Medicine, College of Health Sciences, School of Medicine, Moi University, Eldoret, Kenya
| | - Evangeline Wawira Njiru
- Department of Medicine, College of Health Sciences, School of Medicine, Moi University, Eldoret, Kenya
| | - Willis Dixon Owino Ong’or
- Department of Medicine, College of Health Sciences, School of Medicine, Moi University, Eldoret, Kenya
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12
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Role of plasmatic and urinary concentration of tenofovir disoproxil fumarate in a cohort of patients affected by chronic hepatitis B. Arch Virol 2022; 167:1669-1674. [DOI: 10.1007/s00705-022-05466-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Accepted: 03/26/2022] [Indexed: 11/25/2022]
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13
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Sinakos E, Panas P, Fragkou N, Antoniadis N, Katsanos G, Tsakni E, Oikonomou T, Notopoulos A, Tsoulfas G, Goulis I, Akriviadis E. Tenofovir alafenamide prophylaxis post-liver transplantation: a real-world study in patients with chronic kidney disease. Acta Gastroenterol Belg 2022; 85:331-337. [PMID: 35709777 DOI: 10.51821/85.2.9577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
BACKGROUND & AIMS Tenofovir alafenamide fumarate (TAF) was shown equally efficacious in suppressing hepatitis B virus (HBV) but with less renal toxicity than tenofovir disoproxil fumarate (TDF). The aim of this real-world study was to evaluate renal function in post-liver transplantation (LT) patients that changed TDF with TAF. METHODS The TAF group (n=17) included patients who switched to TAF due to low (<60 ml/min/1.73m2) Glomerular Filtration Rate (GFR). The control group included patients that remained on TDF (n=30), although some (n= 14) had chronic kidney disease (CKD) (TDF-CKD group). GFR was assessed using: i) MDRD-6 variable; ii) CKD-EPI formula; iii) radionuclide technique (rGFR). RESULTS There were no significant differences between the two groups except for the presence of diabetes and follow-up period, which were more common and shorter, respectively, in the TAF group (35% vs. 10%, p=0.03; 13.7 vs. 35.5 months, p<0.001). At the end of follow-up there were no significant changes in renal function between the TAF and the TDF group or TDF-CKD group, although the numerical change in rGFR in the latter comparison was greater in the TAF group (ΔrGFR 3 vs. -2.14 ml/min, p=0.26). The use of everolimus was associated with improvement in renal function (ΔrGFR 2 vs. -7.75 ml/min, p=0.06 [TAF vs. TDF group]; 2 vs. -12 ml/min, p=0.01 [TAF vs. TDF-CKD group]). There were no TAF- related side effects or cases of HBV recurrence. CONCLUSION Conversion to TAF in post-LT patients who develop CKD does not lead to improvement of kidney function after a period of one year.
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Affiliation(s)
- E Sinakos
- 4th Medical Department, Hippokratio Hospital, Aristotle University of Thessaloniki, Greece
| | - P Panas
- 4th Medical Department, Hippokratio Hospital, Aristotle University of Thessaloniki, Greece
| | - N Fragkou
- 4th Medical Department, Hippokratio Hospital, Aristotle University of Thessaloniki, Greece
| | - N Antoniadis
- Department of Transplant Surgery, Hippokratio Hospital, Aristotle University of Thessaloniki, Greece
| | - G Katsanos
- Department of Transplant Surgery, Hippokratio Hospital, Aristotle University of Thessaloniki, Greece
| | - E Tsakni
- Department of Transplant Surgery, Hippokratio Hospital, Aristotle University of Thessaloniki, Greece
| | - T Oikonomou
- 4th Medical Department, Hippokratio Hospital, Aristotle University of Thessaloniki, Greece
| | - A Notopoulos
- Department of Nuclear Medicine, Hippokratio Hospital, Thessaloniki, Greece
| | - G Tsoulfas
- Department of Transplant Surgery, Hippokratio Hospital, Aristotle University of Thessaloniki, Greece
| | - I Goulis
- 4th Medical Department, Hippokratio Hospital, Aristotle University of Thessaloniki, Greece
| | - E Akriviadis
- 4th Medical Department, Hippokratio Hospital, Aristotle University of Thessaloniki, Greece
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14
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Romero‐Cordero S, Noguera‐Julian A, Cardellach F, Fortuny C, Morén C. Mitochondrial changes associated with viral infectious diseases in the paediatric population. Rev Med Virol 2021; 31:e2232. [PMID: 33792105 PMCID: PMC9286481 DOI: 10.1002/rmv.2232] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 02/15/2021] [Accepted: 02/17/2021] [Indexed: 12/24/2022]
Abstract
Infectious diseases occur worldwide with great frequency in both adults and children, causing 350,000 deaths in 2017, according to the latest World Health Organization reports. Both infections and their treatments trigger mitochondrial interactions at multiple levels: (i) incorporation of damaged or mutated proteins into the complexes of the electron transport chain; (ii) impact on mitochondrial genome (depletion, deletions and point mutations) and mitochondrial dynamics (fusion and fission); (iii) membrane potential impairment; (iv) apoptotic regulation; and (v) generation of reactive oxygen species, among others. Such alterations may result in serious adverse clinical events with considerable impact on the quality of life of the children and could even cause death. Herein, we use a systematic review to explore the association between mitochondrial alterations in paediatric infections including human immunodeficiency virus, cytomegalovirus, herpes viruses, various forms of hepatitis, adenovirus, T-cell lymphotropic virus and influenza. We analyse how these paediatric viral infectious processes may cause mitochondrial deterioration in this especially vulnerable population, with consideration for the principal aspects of research and diagnosis leading to improved disease understanding, management and surveillance.
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Affiliation(s)
- Sonia Romero‐Cordero
- Faculty of MedicinePompeu Fabra UniversityBarcelonaSpain
- Faculty of MedicineUniversitat Autònoma de BarcelonaBellaterraSpain
| | - Antoni Noguera‐Julian
- Malalties Infeccioses i Resposta Inflamatòria Sistèmica en PediatriaUnitat d´InfeccionsServei de PediatriaInstitut de Recerca Pediàtrica Hospital Sant Joan de DéuBarcelonaSpain
- Departament de PediatriaUniversitat de BarcelonaBarcelonaSpain
- CIBER de Epidemiología y Salud Pública, CIBERESP (ISCIII)MadridSpain
- Red de Investigación Translacional en Infectología PediátricaRITIPMadridSpain
| | - Francesc Cardellach
- Faculty of Medicine and Health SciencesMuscle Research and Mitochondrial Function LaboratoryCellex‐IDIBAPSUniversity of BarcelonaBarcelonaSpain
- CIBER de Enfermedades RarasCIBERER (ISCIII)MadridSpain
- Internal Medicine DepartmentHospital Clínic of Barcelona (HCB)BarcelonaSpain
| | - Clàudia Fortuny
- Malalties Infeccioses i Resposta Inflamatòria Sistèmica en PediatriaUnitat d´InfeccionsServei de PediatriaInstitut de Recerca Pediàtrica Hospital Sant Joan de DéuBarcelonaSpain
- Departament de PediatriaUniversitat de BarcelonaBarcelonaSpain
- CIBER de Epidemiología y Salud Pública, CIBERESP (ISCIII)MadridSpain
- Red de Investigación Translacional en Infectología PediátricaRITIPMadridSpain
| | - Constanza Morén
- Faculty of Medicine and Health SciencesMuscle Research and Mitochondrial Function LaboratoryCellex‐IDIBAPSUniversity of BarcelonaBarcelonaSpain
- CIBER de Enfermedades RarasCIBERER (ISCIII)MadridSpain
- Internal Medicine DepartmentHospital Clínic of Barcelona (HCB)BarcelonaSpain
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15
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Liu CH, Sun HY, Hsieh SM, Liu WC, Sheng WH, Liu CJ, Su TH, Tseng TC, Chen PJ, Hung CC, Kao JH. Evolution of estimated glomerular filtration rate in human immunodeficiency virus and hepatitis C virus-coinfected patients receiving sofosbuvir-based direct-acting antivirals and antiretroviral therapy. J Viral Hepat 2021; 28:887-896. [PMID: 33759290 DOI: 10.1111/jvh.13502] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 02/06/2021] [Accepted: 02/26/2021] [Indexed: 12/13/2022]
Abstract
The nephrotoxicity of sofosbuvir (SOF) on human immunodeficiency virus and hepatitis C virus (HIV/HCV)-coinfected patients receiving antiretroviral therapy (ART) remains controversial. We prospectively compared the estimated glomerular filtration rate (eGFR) changes in 167 patients receiving SOF-based direct-acting antivirals (DAAs) who also received tenofovir disoproxil fumarate (TFV)-based (n = 116) and TFV-free ART (n = 51). The eGFR was assessed by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, and the eGFR changes between ART regimens were compared by the generalized estimated equation. During DAA treatment, participants on TFV-based ART had a higher eGFR decline than those on TFV-free ART (slope coefficient difference: -0.82 ml/min/1.73 m2 /month [95% CI: -1.21 to -0.43]; p < 0.001), whereas the eGFR changes did not differ between groups (slope coefficient difference: 0.13 ml/min/1.73 m2 /month [95% CI: -0.32 to 0.58]; p = 0.42) after discontinuing DAAs. Participants on TFV TDF-based ART had a higher eGFR decline than those on TFV alafenamide fumarate (TAF)-based ART (slope coefficient difference: -0.31 ml/min/1.73 m2 /month [95% CI: -0.50 to -0.12]; p = 0.01). After discontinuing DAAs, the eGFR changes did not differ between groups (slope coefficient difference: 0.06 ml/min/1.73 m2 /month [95% CI: -0.98 to 1.10]; p = 0.91). In conclusion, HIV/HCV-coinfected patients on TFV-based ART had a slight eGFR decline compared to those on TFV-free ART during SOF-based DAA therapy. A similar trend between TDF-based and TAF-based ART was also observed. Because the differences of eGFR changes are limited, the physicians should not discourage the use of SOF-based DAAs in HIV-positive patients on TFV-based ART.
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Affiliation(s)
- Chen-Hua Liu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.,Department of Internal Medicine, National Taiwan University Hospital, Yun-Lin Branch, Douliou, Taiwan
| | - Hsin-Yun Sun
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Szu-Min Hsieh
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Wen-Chun Liu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Wang-Hui Sheng
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Chun-Jen Liu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.,Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Tung-Hung Su
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Tai-Chung Tseng
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Pei-Jer Chen
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.,Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chien-Ching Hung
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Department of Tropical Medicine and Parasitology, National Taiwan University College of Medicine, Taipei, Taiwan.,Department of Medical Research, China Medical University Hospital, Taichung, Taiwan.,China Medical University, Taichung, Taiwan
| | - Jia-Horng Kao
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.,Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
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16
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Development and Validation of an Up-to-Date Highly Sensitive UHPLC-MS/MS Method for the Simultaneous Quantification of Current Anti-HIV Nucleoside Analogues in Human Plasma. PHARMACEUTICALS (BASEL, SWITZERLAND) 2021; 14:ph14050460. [PMID: 34068180 PMCID: PMC8153023 DOI: 10.3390/ph14050460] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 05/07/2021] [Accepted: 05/11/2021] [Indexed: 11/30/2022]
Abstract
Therapeutic options to treat HIV infection have widened in the past years, improving both effectiveness and tolerability, but nucleoside reverse transcriptase inhibitors (NRTIs) are still considered the standard backbone of the combination regimens. Therapeutic drug monitoring (TDM) can be useful for these drugs, due to concentration–effect relationship, with risk of ineffectiveness, toxicity or adherence concerns: in this scenario, robust and multiplexed methods are needed for an effective TDM activity. In this work, the first validated ultra-high spectrometry liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS) method is described for the high-sensitive simultaneous quantification of all the currently used NRTIs in human plasma, including tenofovir alafenamide (TAF), following FDA and EMA guidelines. The automated sample preparation consisted in the addition of an internal standard (IS) working solution, containing stable-isotope-linked drugs, protein precipitation and drying. Dry extracts were reconstituted with water, then, these underwent reversed phase chromatographic separation: compounds were detected through electrospray ionization and multiple reaction monitoring. Accuracy, precision, recovery and IS-normalized matrix effect fulfilled guidelines’ requirements. The application of this method on samples from people living with HIV (PLWH) showed satisfactory performance, being capable of quantifying the very low concentrations of tenofovir (TFV) in patients treated with TAF.
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17
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Lanman T, Letendre S, Ma Q, Bang A, Ellis R. CNS Neurotoxicity of Antiretrovirals. J Neuroimmune Pharmacol 2021; 16:130-143. [PMID: 31823251 PMCID: PMC7282963 DOI: 10.1007/s11481-019-09886-7] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Accepted: 10/01/2019] [Indexed: 12/20/2022]
Abstract
The development of novel antiretroviral treatments has led to a significant turning point in the fight against HIV. Although therapy leads to virologic suppression and prolonged life expectancies, HIV-associated neurocognitive disorder (HAND) remains prevalent. While various hypotheses have been proposed to explain this phenomenon, a growing body of literature explores the neurotoxic effects of antiretroviral therapy. Research to date brings into question the potential role of such medications in neurocognitive and neuropsychiatric impairment seen in HIV-positive patients. This review highlights recent findings and controversies in cellular, molecular, and clinical neurotoxicity of antiretrovirals. It explores the pathogenesis of such toxicity and relates it to clinical manifestations in each medication class. The concept of accelerated aging in persons living with HIV (PLWH) as well as potential treatments for HAND are also discussed. Ultimately, this article hopes to educate clinicians and basic scientists about the neurotoxic effects of antiretrovirals and spur future scientific investigation into this important topic. Graphical Abstract.
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Affiliation(s)
- Tyler Lanman
- Department of Neurosciences, University of California San Diego School of Medicine, 200 W Arbor Dr, San Diego, La Jolla, CA, 92103, USA
| | - Scott Letendre
- Department of Infectious Diseases, University of California San Diego School of Medicine, La Jolla, CA, USA
| | - Qing Ma
- Pharmacotherapy Research Center, University of Buffalo, School of Pharmacy & Pharmaceutical Sciences, Buffalo, NY, USA
| | - Anne Bang
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - Ronald Ellis
- Department of Neurosciences, University of California San Diego School of Medicine, 200 W Arbor Dr, San Diego, La Jolla, CA, 92103, USA.
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18
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Brayette A, Essig M, Carrier P, Debette-Gratien M, Labrunie A, Alain S, Maynard M, Ganne-Carrié N, Nguyen-Khac E, Pinet P, De Ledinghen V, Renou C, Mathurin P, Vanlemmens C, Di Martino V, Gervais A, Foucher J, Isabelle FH, Vergniol J, Hourmand-Ollivier I, Cohen D, Duval X, Poynard T, Bardou M, Abergel A, Dao MT, Thévenot T, Hiriart JB, Canva V, Lassailly G, Aurières C, Boyer N, Thabut D, Bernard PH, Schnee M, Larrey D, Hanslik B, Hommel S, Jacques J, Loustaud-Ratti V. Subclinical proximal tubulopathy in hepatitis B: The roles of nucleot(s)ide analogue treatment and the hepatitis B virus. World J Hepatol 2020; 12:1326-1340. [PMID: 33442458 PMCID: PMC7772739 DOI: 10.4254/wjh.v12.i12.1326] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 10/07/2020] [Accepted: 10/28/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The recommended monitoring tools for evaluating nucleot(s)ide analogue renal toxicity, such as estimated glomerular filtration rate (eGFR) and phosphatemia, are late markers of proximal tubulopathy. Multiple early markers are available, but no consensus exists on their use.
AIM To determine the 24 mo prevalence of subclinical proximal tubulopathy (SPT), as defined with early biomarkers, in treated vs untreated hepatitis B virus (HBV)-monoinfected patients.
METHODS A prospective, non-randomized, multicenter study of HBV-monoinfected patients with a low number of renal comorbidities was conducted. The patients were separated into three groups: Naïve, starting entecavir (ETV) treatment, or starting tenofovir disoproxil (TDF) treatment. Data on the early markers of SPT, the eGFR and phosphatemia, were collected quarterly. SPT was defined as a maximal tubular reabsorption of phosphate/eGFR below 0.8 mmoL/L and/or uric acid fractional excretion above 10%. The prevalence and cumulative incidence of SPT at month 24 (M24) were calculated. Quantitative data were analyzed using analyses of variance or Kruskal-Wallis tests, whereas chi-squared or Fisher’s exact tests were used to analyze qualitative data. Multivariate analyses were used to adjust for any potential confounding factors.
RESULTS Of the 196 patients analyzed, 138 (84 naïve, 28 starting ETV, and 26 starting TDF) had no SPT at inclusion. At M24, the prevalence of SPT was not statistically different between naïve and either treated group (21.1% vs 30.7%, P < 0.42 and 50.0% vs 30.7%, P = 0.32 for ETV and TDF, respectively); no patient had an eGFR lower than 50 mL/min/1.73 m² or phosphatemia less than 0.48 mmoL/L. In the multivariate analysis, no explanatory variables were identified after adjustment. The cumulative incidence of SPT over 24 mo (25.5%, 13.3%, and 52.9% in the naïve, ETV, and TDF groups, respectively) tended to be higher in the TDF group vs the naïve group (hazard ratio: 2.283, P = 0.05). SPT-free survival at M24 was 57.6%, 68.8%, and 23.5% for the naïve, ETV, and TDF groups, respectively. The median survival time without SPT, evaluated only in the TDF group, was 5.9 mo.
CONCLUSION The prevalence and incidence of SPT was higher in TDF-treated patients compared to naïve patients. SPT in the naïve population suggests that HBV can induce renal tubular toxicity.
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Affiliation(s)
- Anaïs Brayette
- U1248 INSERM, Department of Hepatology and Gastroenterology, Univ. Limoges, CHU Limoges, Limoges F-87000, France
| | - Marie Essig
- U1248 INSERM, Department of Nephrology and Transplantation, CHU Limoges, Limoges F-87000, France
| | - Paul Carrier
- U1248 INSERM, Department of Hepatology and Gastroenterology, Univ. Limoges, CHU Limoges, Limoges F-87000, France
| | - Marilyne Debette-Gratien
- U1248 INSERM, Department of Hepatology and Gastroenterology, Univ. Limoges, CHU Limoges, Limoges F-87000, France
| | - Anaïs Labrunie
- Department of Center of Epidemiology, Biostatistics and Research Methodology, CHU Limoges, Limoges F-87000, France
| | - Sophie Alain
- U1092 INSERM, Department of Virology, CHU Limoges, Limoges F-87000, France
| | - Marianne Maynard
- Department of Hepatology, Croix-Rousse University Hospital of Lyon, Lyon 69004, France
| | - Nathalie Ganne-Carrié
- Department of Hepatology, Jean Verdier University Hospital of Bondy, Bondy 93140, France
| | - Eric Nguyen-Khac
- Department of Hepato-Gastroenterology, Amiens University Hospital, Amiens 80054, France
| | - Pauline Pinet
- Department of Infectious Diseases, CHU Limoges, Limoges F-87000, France
| | - Victor De Ledinghen
- Department of Hepatology, Haut Leveque Hospital, Bordeaux University Hospital, Pessac 33604, France
| | - Christophe Renou
- Department of Gastroenterology, Hyeres Hospital, Hyeres 83407, France
| | - Philippe Mathurin
- Department of Hepato-Gastroenterology, Claude Huriez University Hospital, Lille 59037, France
| | - Claire Vanlemmens
- Department of Hepatology, Jean Minjoz University Hospital, Besançon 25030, France
| | - Vincent Di Martino
- Department of Hepatology, Jean Minjoz University Hospital, Besançon 25030, France
| | - Anne Gervais
- Department of Infectious Diseases, Bichat University Hospital, Paris 75018, France
| | - Juliette Foucher
- Department of Hepatology, Haut Leveque Hospital, Bordeaux University Hospital, Pessac 33604, France
| | | | - Julien Vergniol
- Department of Hepatology, Haut Leveque Hospital, Bordeaux University Hospital, Pessac 33604, France
| | | | - Daniel Cohen
- Department of General Medecine, University Hospital of Caen, Caen 14000, France
| | - Xavier Duval
- Department of Infectious Diseases, Bichat University Hospital, Paris 75018, France
| | - Thierry Poynard
- Department of Hepatology, La Pitié-Salpêtrière University Hospital, Paris 75651, France
| | - Marc Bardou
- Department of Hepatology and Gastroenterology, Dijon University Hospital, Dijon 21079, France
| | - Armand Abergel
- Department of Hepatology and Gastroenterology, Estaing University Hospital, Clermont Ferrand 63003, France
| | - Manh-Thong Dao
- Department of Hepato-Gastroenterology and Nutrition, University Hospital of Caen, Caen 14033, France
| | - Thierry Thévenot
- Department of Hepatology, Jean Minjoz University Hospital, Besançon 25030, France
| | - Jean-Baptiste Hiriart
- Department of Hepatology, Haut Leveque Hospital, Bordeaux University Hospital, Pessac 33604, France
| | - Valérie Canva
- Department of Hepato-Gastroenterology, Claude Huriez University Hospital, Lille 59037, France
| | - Guillaume Lassailly
- Department of Hepato-Gastroenterology, Claude Huriez University Hospital, Lille 59037, France
| | - Christine Aurières
- Department of Hepatology, Beaujon University Hospital, Clichy 92110, France
| | - Nathalie Boyer
- Department of Hepatology, Beaujon University Hospital, Clichy 92110, France
| | - Dominique Thabut
- Department of Hepatology, La Pitié-Salpêtrière University Hospital, Paris 75651, France
| | - Pierre-Henri Bernard
- Department of Hepatology, Saint-André University Hospital, Bordeaux 33000, France
| | - Matthieu Schnee
- Department of Hepatology and Gastroenterology, La Roche-Sur-Yon Hospital Center, La Roche-Sur-Yon 85000, France
| | - Dominique Larrey
- Department of Hepatology and Gastroenterology, University Hospital of Montpellier, Montpellier 34295, France
| | - Bertrand Hanslik
- Department of Addictology, Hospital of Montpellier, Montpellier 34295, France
| | - Séverine Hommel
- Department of Hepatology and Gastroenterology, Hospital Center of Aix en Provence, Aix-en-Provence 13100, France
| | - Jérémie Jacques
- U1248 INSERM, Department of Hepatology and Gastroenterology, Univ. Limoges, CHU Limoges, Limoges F-87000, France
| | - Véronique Loustaud-Ratti
- U1248 INSERM, Department of Hepatology and Gastroenterology, Univ. Limoges, CHU Limoges, Limoges F-87000, France
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Renal Dysfunction and Tubulopathy Induced by High-Dose Tenofovir Disoproxil Fumarate in C57BL/6 Mice. Healthcare (Basel) 2020; 8:healthcare8040417. [PMID: 33096887 PMCID: PMC7711546 DOI: 10.3390/healthcare8040417] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 10/18/2020] [Accepted: 10/19/2020] [Indexed: 12/05/2022] Open
Abstract
Tenofovir disoproxil fumarate (TDF) is the most preferred antiretroviral medicine in treating human immunodeficiency virus (HIV) and hepatitis B virus (HBV) infections. Recent clinical trials have reported conflicting results on renal toxicity and safety in TDF-treated patients, but reference animal studies, testing high-doses of TDF for renal toxicity, are scarce. In this preclinical study, we investigated whether daily oral TDF administration (200, 500, or 800 mg/kg/d, p.o.) for four weeks induces renal insufficiency in C57BL/6 mice, by evaluating changes in body weight, urine micro-total protein, urinary microalbumin, serum blood urea nitrogen (BUN), and creatinine levels, along with histological examination of kidney samples. In the G3 group (TDF 800 mg/kg/d, p.o.), three mice died on the 17th, 23rd and 26th days, and overall, significant increases in urinary and serum levels were observed after two weeks of TDF treatment. In addition, the proportion of pyknotic epithelial cells and acidophilic cytoplasm in renal tubules was also increased after two weeks, and congestion and hemorrhage were observed in renal tubules after three weeks. Taken together, high-dose TDF treatment of 800 mg/kg/d might lead to renal tubular damage and dysfunction, great enough to cause death in mice, even after a short period of one to two weeks.
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Hassan MO, Duarte R, Mabayoje VO, Dickens C, Lasisi AO, Naicker S. Design and methods of the prevalence and pharmacogenomics of tenofovir nephrotoxicity in HIV-positive adults in south-western Nigeria study. BMC Nephrol 2020; 21:436. [PMID: 33066744 PMCID: PMC7565751 DOI: 10.1186/s12882-020-02082-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Accepted: 09/30/2020] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Individuals of African descent are at higher risk of developing kidney disease than their European counterparts, and HIV infection is associated with increased risk of nephropathy. Despite a safe renal profile in the clinical trials, long-term use of tenofovir disoproxil fumarate (TDF) has been associated with proximal renal tubulopathy although the underlying mechanisms remain undetermined. We aim to establish the prevalence of and risk factors for TDF-induced kidney tubular dysfunction (KTD) among HIV-I and II individuals treated with TDF in south-west Nigeria. Association between TDF-induced KTD and genetic polymorphisms in renal drug transporter genes and the APOL1 (Apolipoprotein L1) gene will be examined. METHODS This study has two phases. An initial cross-sectional study will screen 3000 individuals attending the HIV clinics in south-west Nigeria for KTD to determine the prevalence and risk factors. This will be followed by a case-control study of 400 KTD cases and 400 matched controls to evaluate single nucleotide polymorphism (SNP) associations. Data on socio-demographics, risk factors for kidney dysfunction and HIV history will be collected by questionnaire. Blood and urine samples for measurements of severity of HIV disease (CD4 count, viral load) and renal function (creatinine, eGFR, phosphate, uric acid, glucose) will also be collected. Utility of urinary retinol binding protein (RBP) and N-acetyl-beta-D-glucosaminidase (NAG) levels as surrogate markers of KTD will be evaluated. Genomic DNA will be extracted from whole blood and SNP analyses performed using the rhAMP SNP genotyping assays. Statistical analysis including univariate and multivariate logistic regression analyses will be performed to identify factors associated with KTD. DISCUSSION In spite of TDF being the most commonly used antiretroviral agent and a key component of many HIV treatment regimens, it has potential detrimental effects on the kidneys. This study will establish the burden and risk factors for TDF-induced KTD in Nigerians, and explore associations between KTD and polymorphisms in renal transporter genes as well as APOL1 risk variants. This study may potentially engender an approach for prevention as well as stemming the burden of CKD in sub-Saharan Africa where GDP per capita is low and budgetary allocation for health is inadequate.
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Affiliation(s)
- Muzamil O Hassan
- Department of Internal Medicine, Ladoke Akintola University of Technology Teaching Hospital, Osogbo, Nigeria.
- Department of Medicine, Obafemi Awolowo University, Ile-Ife, Osun State, Nigeria.
| | - Raquel Duarte
- Internal Medicine Research Laboratory, Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Victor O Mabayoje
- Department of Haematology, Ladoke Akintola University of Technology Teaching Hospital, Osogbo, Nigeria
| | - Caroline Dickens
- Internal Medicine Research Laboratory, Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Akeem O Lasisi
- Department of OtoRhinoLaryngology, University College Hospital, Ibadan, Nigeria
| | - Saraladevi Naicker
- Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
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21
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Gaut JP, Liapis H. Acute kidney injury pathology and pathophysiology: a retrospective review. Clin Kidney J 2020; 14:526-536. [PMID: 33623675 PMCID: PMC7886540 DOI: 10.1093/ckj/sfaa142] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Indexed: 12/12/2022] Open
Abstract
Acute kidney injury (AKI) is the clinical term used for decline or loss of renal function. It is associated with chronic kidney disease (CKD) and high morbidity and mortality. However, not all causes of AKI lead to severe consequences and some are reversible. The underlying pathology can be a guide for treatment and assessment of prognosis. The Kidney Disease: Improving Global Outcomes guidelines recommend that the cause of AKI should be identified if possible. Renal biopsy can distinguish specific AKI entities and assist in patient management. This review aims to show the pathology of AKI, including glomerular and tubular diseases.
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Affiliation(s)
- Joseph P Gaut
- Department of Pathology and Immunology and Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Helen Liapis
- Department of Pathology and Immunology and Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
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22
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Duraisamy GS, Bhosale D, Lipenská I, Huvarova I, Růžek D, Windisch MP, Miller AD. Advanced Therapeutics, Vaccinations, and Precision Medicine in the Treatment and Management of Chronic Hepatitis B Viral Infections; Where Are We and Where Are We Going? Viruses 2020; 12:v12090998. [PMID: 32906840 PMCID: PMC7552065 DOI: 10.3390/v12090998] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 08/31/2020] [Accepted: 09/02/2020] [Indexed: 02/06/2023] Open
Abstract
The management of chronic hepatitis B virus (CHB) infection is an area of massive unmet clinical need worldwide. In spite of the development of powerful nucleoside/nucleotide analogue (NUC) drugs, and the widespread use of immune stimulators such as interferon-alpha (IFNα) or PEGylated interferon-alpha (PEG-IFNα), substantial improvements in CHB standards of care are still required. We believe that the future for CHB treatment now rests with advanced therapeutics, vaccination, and precision medicine, if all are to bring under control this most resilient of virus infections. In spite of a plethora of active drug treatments, anti-viral vaccinations and diagnostic techniques, the management of CHB infection remains unresolved. The reason for this is the very complexity of the virus replication cycle itself, giving rise to multiple potential targets for therapeutic intervention some of which remain very intractable indeed. Our review is focused on discussing the potential impact that advanced therapeutics, vaccinations and precision medicine could have on the future management of CHB infection. We demonstrate that advanced therapeutic approaches for the treatment of CHB, in the form of gene and immune therapies, together with modern vaccination strategies, are now emerging rapidly to tackle the limitations of current therapeutic approaches to CHB treatment in clinic. In addition, precision medicine approaches are now gathering pace too, starting with personalized medicine. On the basis of this, we argue that the time has now come to accelerate the design and creation of precision therapeutic approaches (PTAs) for CHB treatment that are based on advanced diagnostic tools and nanomedicine, and which could maximize CHB disease detection, treatment, and monitoring in ways that could genuinely eliminate CHB infection altogether.
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Affiliation(s)
- Ganesh Selvaraj Duraisamy
- Veterinary Research Institute, Hudcova 70, CZ-62100 Brno, Czech Republic; (G.S.D.); (D.B.); (I.L.); (I.H.); (D.R.)
| | - Dattatry Bhosale
- Veterinary Research Institute, Hudcova 70, CZ-62100 Brno, Czech Republic; (G.S.D.); (D.B.); (I.L.); (I.H.); (D.R.)
| | - Ivana Lipenská
- Veterinary Research Institute, Hudcova 70, CZ-62100 Brno, Czech Republic; (G.S.D.); (D.B.); (I.L.); (I.H.); (D.R.)
| | - Ivana Huvarova
- Veterinary Research Institute, Hudcova 70, CZ-62100 Brno, Czech Republic; (G.S.D.); (D.B.); (I.L.); (I.H.); (D.R.)
| | - Daniel Růžek
- Veterinary Research Institute, Hudcova 70, CZ-62100 Brno, Czech Republic; (G.S.D.); (D.B.); (I.L.); (I.H.); (D.R.)
- Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, Branisovska 31, CZ-37005 České Budějovice, Czech Republic
| | - Marc P. Windisch
- Applied Molecular Virology Laboratory, Institut Pasteur Korea, 696 Sampyeong-dong, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Korea;
- Division of Bio-Medical Science and Technology, University of Science and Technology, Daejeon 305-350, Korea
| | - Andrew D. Miller
- Veterinary Research Institute, Hudcova 70, CZ-62100 Brno, Czech Republic; (G.S.D.); (D.B.); (I.L.); (I.H.); (D.R.)
- Department of Chemistry and Biochemistry, Mendel University in Brno, Zemědělská 1, Černá Pole, CZ-61300 Brno, Czech Republic
- KP Therapeutics (Europe) s.r.o., Purkyňova 649/127, CZ-61200 Brno, Czech Republic
- Correspondence:
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Japan Society of Hepatology Guidelines for the Management of Hepatitis B Virus Infection: 2019 update. Hepatol Res 2020; 50:892-923. [PMID: 32343469 DOI: 10.1111/hepr.13504] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 03/16/2020] [Accepted: 03/22/2020] [Indexed: 02/06/2023]
Abstract
The Drafting Committee for Hepatitis Management Guidelines established by the Japan Society of Hepatology published the first version of the Guidelines for the Management of Hepatitis B in 2013 (first English version in 2014), and has since been publishing updates to the Guidelines as new drugs become available, with the latest original Japanese version being Version 3.1. Herein, the Drafting Committee publishes the second English version that contains all the changes made since the first English version of the guidelines was published in 2014. This 2019 version covers: (i) the nucleos(t)ide analogs, tenofovir disoproxil fumarate and tenofovir alafenamide; (ii) updates to treatment recommendations and management of drug-resistant hepatitis B virus that reflect the new availability of these drugs; and (iii) new information about hepatitis B virus reactivation with each update. This latest update also contains information about treatment goals, indications for treatment and cessation of nucleos(t)ide analog therapy, most of which were covered by the first version.
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Kichloo A, Chugh SS, Gupta S, Panday J, Goldar GE. Tenofovir and Severe Symptomatic Hypophosphatemia. J Investig Med High Impact Case Rep 2020; 7:2324709619848796. [PMID: 31142127 PMCID: PMC6545665 DOI: 10.1177/2324709619848796] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Tenofovir is a broadly used drug used for the treatment of human immunodeficiency virus (HIV). Although the initial results of the clinical trials supported the renal safety of Tenofovir, clinical use of it has caused a low, albeit a significant, risk of renal damage either in the form of AKI or CKD. The pathophysiology has been linked to the effect of this medication on the proximal tubular cell. Although the exact mechanism is unknown, studies have suggested that Tenofovir accumulates in proximal tubular cells which are rich in mitochondria. It is both filtered in the glomerulus and actively secreted in the tubules for elimination and is excreted unchanged in the urine. Studies have shown an active transportation of 20-30% of this drug into the renal proximal tubule (PCT) cells via the organic anion transporters in the baso-lateral membrane (primarily hOAT1, and OAT3 to a lesser extent) and ultimate excretion of the drug into the tubular lumen via the transporters in the proximal tubular apical membrane MRP4 and MRP2 (multidrug resistance-associated proteins 2 & 4). Subsequently, the mitochondrial injury caused by Tenofovir can lead to the development of Fanconi's syndrome which causes renal tubular acidosis, phosphaturia, aminoaciduria, glucosuria with normoglycemia, and tubular proteinuria. Here we present a case where Tenofovir treatment resulted in severe hypophosphatemia requiring hospitalization for parentral phosphate repletion.
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Affiliation(s)
- Asim Kichloo
- 1 St. Mary's Hospital, Saginaw, MI, USA.,2 Central Michigan University, Mount Pleasant, MI, USA
| | - Savneek Singh Chugh
- 3 Westchester Medical Center, Valhalla, NY, USA.,4 Newyork Medical College, Valhalla, NY, USA
| | - Sanjeev Gupta
- 3 Westchester Medical Center, Valhalla, NY, USA.,4 Newyork Medical College, Valhalla, NY, USA
| | - Jay Panday
- 3 Westchester Medical Center, Valhalla, NY, USA.,4 Newyork Medical College, Valhalla, NY, USA
| | - Ghazaleh Emedis Goldar
- 1 St. Mary's Hospital, Saginaw, MI, USA.,2 Central Michigan University, Mount Pleasant, MI, USA
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Guo H, Liu J, Pu L, Hao J, Yin N, Liu Y, Xiong H, Li A. Continuous renal replacement therapy in patients with HIV/AIDS. BMC Nephrol 2020; 21:95. [PMID: 32160882 PMCID: PMC7066780 DOI: 10.1186/s12882-020-01754-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Accepted: 02/28/2020] [Indexed: 11/28/2022] Open
Abstract
Background Acute kidney injury (AKI) is a common complication among human immunodeficiency virus (HIV)-infected patients resulting in increased morbidity and mortality. Continuous renal replacement therapy (CRRT) is a useful method and instrument in critically ill patients with fluid overload and metabolic disarray, especially in those who are unable to tolerate the intermittent hemodialysis. However, the epidemiology, influence factors of CRRT and mortality in patients with HIV/AIDS are still unclear in China. This study aims to study the HIV-infected patients admitted in Intensive Care Unit (ICU) and explore the influence factors correlated with CRRT and their prognosis. Methods We performed a retrospective case-control study in the ICU of the Beijing Ditan Hospital Capital Medical University. From June 1, 2005 to May 31, 2017, 225 cases were enrolled in this clinical study. Results 122 (54.2%) patients were diagnosed with AKI during their stay in ICU, the number and percentage of AKI stage 1, 2 and 3 were 38 (31.1%), 21(17.2%) and 63(51.7%), respectively. 26.2% of AKI patients received CRRT during the stay of ICU. 56.25% CRRT patients died in ICU. The 28-day mortality was 62.5%, and the 90-day mortality was 75%. By univariate logistics analysis, it showed that higher likelihood of diagnosis for respiratory failure (OR = 7.333,95% CI 1.467–36.664, p = 0.015), higher likelihood of diagnosis for septic shock (OR = 1.005,95% CI 1.001–1.01, p = 0.018), and higher likelihood to use vasoactive agents (OR = 10.667,95% CI 1.743–65.271, p = 0.001), longer mechanical ventilation duration (OR = 1.011,95% CI 1.002–1.019, p = 0.011), higher likelihood for diagnosis for PCP (OR = 7.50,95% CI 1.288–43.687, p = 0.025), higher SOFA score at ICU admission (OR = 1.183,95% CI 1.012–1.383, p = 0.035), longer duration of CRRT (OR = 1.014,95% CI 1.001–1.028, p = 0.034) contributed to a higher mortality at ICU. The Cox Analysis for the cumulative survival of AKI 3 patients between the CRRT and non-CRRT groups shows no significant differences (p = 0.595). Conclusions There is a high incidence of AKI in HIV-infected patients admitted in our ICU. Patients with severe AKI were more prone to be admitted for CRRT and have a consequent poor prognosis.
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Affiliation(s)
- Hebing Guo
- Department of Critical Care Medicine, Beijing Ditan Hospital, Capital Medical University, No. 8 Jingshundong Street, Beijing, 100015, Chaoyang District, China
| | - Jingyuan Liu
- Department of Critical Care Medicine, Beijing Ditan Hospital, Capital Medical University, No. 8 Jingshundong Street, Beijing, 100015, Chaoyang District, China
| | - Lin Pu
- Department of Critical Care Medicine, Beijing Ditan Hospital, Capital Medical University, No. 8 Jingshundong Street, Beijing, 100015, Chaoyang District, China
| | - Jingjing Hao
- Department of Critical Care Medicine, Beijing Ditan Hospital, Capital Medical University, No. 8 Jingshundong Street, Beijing, 100015, Chaoyang District, China
| | - Ningning Yin
- Department of Critical Care Medicine, Beijing Ditan Hospital, Capital Medical University, No. 8 Jingshundong Street, Beijing, 100015, Chaoyang District, China
| | - Yufeng Liu
- Department of Critical Care Medicine, Beijing Ditan Hospital, Capital Medical University, No. 8 Jingshundong Street, Beijing, 100015, Chaoyang District, China
| | - Haofeng Xiong
- Department of Critical Care Medicine, Beijing Ditan Hospital, Capital Medical University, No. 8 Jingshundong Street, Beijing, 100015, Chaoyang District, China
| | - Ang Li
- Department of Critical Care Medicine, Beijing Ditan Hospital, Capital Medical University, No. 8 Jingshundong Street, Beijing, 100015, Chaoyang District, China.
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Liang RY, Xu JH, Si CW, Wang S, Shang J, Yu ZJ, Mao Q, Xie Q, Zhao W, Li J, Gao ZL, Wu SM, Tang H, Cheng J, Chen XY, Zhang WH, Wang H, Xu ZN, Wang L, Dai J, Yu YY. A randomized, double-blind, double-dummy, controlled, multicenter study of Qingzhong (tenofovir disoproxil fumarate) versus Viread for the treatment of chronic hepatitis B: First-stage results at week 48. Medicine (Baltimore) 2019; 98:e16778. [PMID: 31415381 PMCID: PMC6831396 DOI: 10.1097/md.0000000000016778] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Tenofovir disoproxil fumarate (TDF) has been widely recommended as a first-line antiviral agent to treat chronic hepatitis B (CHB). Qingzhong and Viread, formulations of TDF commercialized by Jiangsu Chia-tai Tianqing Pharmaceutical Co Ltd and GlaxoSmithKline, respectively, have both been approved by the State Food and Drug Administration, China. This study analyzed the efficacy and safety of these 2 TDF agents in Chinese patients with CHB. METHODS In this multicenter, randomized, double-blind, double-dummy, noninferiority phase 3 clinical trial (ClinicalTrials.gov identifier: NCT02287857), 330 Chinese patients with CHB [hepatitis B envelope antigen-positive (HBeAg) (+): 232] were randomly assigned to receive Qingzhong (group A: 161 patients) or Viread (group B: 169 patients) 300 mg once daily for 48 weeks. Subsequently, all patients were administered Qingzhong 300 mg once daily from week 49 to week 240. The primary end point was the degree of decline of plasma hepatitis B virus (HBV) DNA levels at week 48 and the secondary endpoints were viral suppression, normalization of alanine aminotransferase (ALT) levels, hepatitis B surface antigen (HBsAg)/HBeAg loss or seroconversion, and virological breakthrough. RESULTS Among patients with CHB who were HBeAg (+), the mean HBV DNA titer decreased similarly between the groups at week 48. The percentages of patients who achieved undetectable HBV DNA were similar between the groups (85.11% and 82.35% in groups A and B, respectively) and similar losses of HBeAg and HBeAg seroconversion rates were achieved. Moreover, for patients with CHB who were HBeAg (-), reductions in HBV DNA were similar. Among all patients with CHB, the rates of normalization of ALT and the loss of HBsAg were similar. The overall incidence of adverse events was comparable between the groups. CONCLUSION In conclusion, the 48-week administration of Qingzhong showed noninferior efficacy and safety profiles compared to Viread in Chinese patients with CHB.
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Affiliation(s)
- Rong-Yue Liang
- Department of Infectious Diseases, Center for Liver Diseases, Peking University First Hospital, Peking
| | - Jing-Hang Xu
- Department of Infectious Diseases, Center for Liver Diseases, Peking University First Hospital, Peking
| | - Chong-Wen Si
- Department of Infectious Diseases, Center for Liver Diseases, Peking University First Hospital, Peking
| | - Sa Wang
- Department of Infectious Diseases, Center for Liver Diseases, Peking University First Hospital, Peking
| | - Jia Shang
- Department of Infectious Diseases, Henan Provincial People's Hospital
| | - Zu-Jiang Yu
- Department of Infectious Diseases, First Affiliated Hospital of Zhengzhou University, Henan
| | - Qing Mao
- Department of Infectious Diseases, Southwest China Hospital, Chongqing
| | - Qing Xie
- Department of Infectious Diseases, Ruijin Hospital, Jiaotong University School of Medicine, Shanghai
| | - Wei Zhao
- Department of Infectious Diseases, The Second Affiliated Hospital of Southeast University
| | - Jun Li
- Department of Infectious Diseases, The First Affiliated Hospital with Nanjing Medical University, Nanjing
| | - Zhi-Liang Gao
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangdong
| | - Shan-Ming Wu
- Department of Infectious Diseases, Shanghai Public Health Clinical Center, Fudan University, Shanghai
| | - Hong Tang
- Department of Infectious Diseases, West China Hospital of Sichuan University, Sichuan
| | - Jun Cheng
- Department of Infectious Diseases, Beijing Ditan Hospital
| | - Xin-Yue Chen
- Department of International Medicine, Beijing Youan Hospital, Capital Medical University, Beijing
| | - Wen-Hong Zhang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai
| | - Hao Wang
- Department of Infectious Diseases, Peking University People's Hospital, Beijing
| | - Zhong-Nan Xu
- Jiangsu Chia-tai Tianqing Pharmaceutical Co, Ltd, Nanjing, China
| | - Ling Wang
- Jiangsu Chia-tai Tianqing Pharmaceutical Co, Ltd, Nanjing, China
| | - Jun Dai
- Jiangsu Chia-tai Tianqing Pharmaceutical Co, Ltd, Nanjing, China
| | - Yan-Yan Yu
- Department of Infectious Diseases, Center for Liver Diseases, Peking University First Hospital, Peking
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Domingo P, Suarez-Lozano I, Gutierrez F, Estrada V, Knobel H, Palacios R, Antela A, Blanco JR, Fulladosa X. Predictive factors of renal impairment in HIV-infected patients on antiretroviral therapy: Results from the VACH longitudinal cohort study. Nefrologia 2019; 39:497-505. [PMID: 31027896 DOI: 10.1016/j.nefro.2019.01.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Revised: 11/23/2018] [Accepted: 01/14/2019] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND The use of combination antiretroviral therapy has led to dramatic improvements in the life expectancy of HIV-infected persons. As result, the HIV population is aging and increasingly facing illnesses typically seen in the elderly, such as chronic kidney disease (CKD). METHODS A retrospective longitudinal study was conducted using data from years 2010 and 2014 in all HIV-infected persons enrolled at the Spanish VACH cohort. We analyzed the prevalence and the predictive factors for developing CKD (estimated glomerular filtration rate, eGFR<60mL/min/1.73m2). RESULTS The CKD prevalence at baseline was 456/8968, 5.1% [4.6-5.6%]. Of 8512 HIV-positive individuals examined without CKD at baseline (73.7% male, median age 44 years-old), 2.15% developed CKD (eGFR<60mL/min/1.73m2). The odds ratios [95%CI] for the independent predictive factors identified were gender (male) 0.54 [0.39-0.75], age (per year) 1.08 [1.07-1.10], AIDS diagnosis 1.40 [1.03-1.91], protease inhibitor-based regimens 1.49 [1.10-2.02], hypertension 1.37 [0.94-1.99], diabetes 1.84 [1.33-2.55] and history of cardiovascular events 1.66 [0.96-2.86]. CONCLUSION The prevalence and risk factors for CKD and its progression are high in the VACH cohort. Thus, preventive measures such as control of hypertension, diabetes and obesity, as well as efforts for avoiding exposure to nephrotoxic drugs, including some antiretrovirals, are warranted in this aging HIV population.
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Affiliation(s)
- Pere Domingo
- Infectious Diseases Unit, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
| | | | - Félix Gutierrez
- Infectious Diseases Unit, Hospital Universitario de Elche, Alicante, Spain
| | - Vicente Estrada
- Infectious Diseases Unit, Hospital Clínico San Carlos, Madrid, Spain
| | - Hernando Knobel
- Infectious Diseases Unit, Hospital del Mar, Barcelona, Spain
| | - Rosario Palacios
- Infectious Diseases Unit, Hospital Universitario Virgen de la Victoria, Malaga, Spain
| | - Antonio Antela
- Infectious Diseases Unit, Complexo Hospitalario Universitario, Santiago de Compostela, Spain
| | | | - Xavier Fulladosa
- Nephrology Unit, Hospital Universitario de Bellvitge, Barcelona, Spain
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Casado JL, Santiuste C, Vivancos MJ, Monsalvo M, Moreno A, Perez-Elías MJ, Del Rey JM, Moreno S. Switching to abacavir versus use of a nucleoside-sparing dual regimen for HIV-infected patients with tenofovir-associated renal toxicity. HIV Med 2018; 19:541-550. [PMID: 29932293 DOI: 10.1111/hiv.12630] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/11/2018] [Indexed: 11/27/2022]
Abstract
OBJECTIVES We investigated the reversibility of tenofovir disoproxil fumarate (TDF)-associated renal decline and tubular dysfunction using different antiretroviral strategies. METHODS A successive evaluation of renal [estimated glomerular filtration rate (eGFR)] and tubular (phosphataemia, proteinuria, albuminuria, phosphaturia, uricosuria, glycosuria and tubular proteinuria) parameters was performed in 231 patients, before and after switching from TDF to abacavir (n = 60), using dual therapy (n = 49), or continuing the same regimen including TDF (n = 122). RESULTS In a successive evaluation after a median of 8.86 months, or less time if treatment was switched (4.8 months vs. 13.3 months to second evaluation; P < 0.01), a significant improvement in eGFR (median change +0.3 vs. -2.91 mL/min/1.73 m2 in patients who did not discontinue TDF; P = 0.04) and tubular dysfunction (median change -40% vs. +30%, respectively; P < 0.01) was observed. Lineal regression showed that age (β = -0.14; P = 0.04), previous eGFR decline (β = -0.42; P < 0.01), and time on TDF (β = -0.19; P = 0.04) were associated with impaired eGFR recovery. There were no differences in eGFR slopes between patients using abacavir instead of TDF and those using a dual therapy, who showed similar improvement in proteinuria (-22% vs. -19%, respectively), phosphaturia (+10.1% vs. +9.4%, respectively), and urinary beta-2-microglobulin (-9% vs. -15%, respectively; P > 0.1 for all), although patients receiving the dual regimen were more heavily pretreated. A eGFR decrease (-6.17 mL/min/1.73 m2 ) was observed in patients taking dolutegravir or rilpivirine, but with similar improvement to that observed in the rest of switching patients in tubular abnormalities. CONCLUSIONS Tenofovir disoproxil fumarate discontinuation was associated with a rapid and significant improvement in eGFR and tubular abnormalities, regardless of whether abacavir or dual therapy was chosen. Switching to a regimen that included dolutegravir and/or rilpivirine was associated with a eGFR decrease without differences in the rate of tubular dysfunction improvement in comparison with the rest of patients who discontinued tenofovir.
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Affiliation(s)
- J L Casado
- Department of Infectious Diseases and Biochemistry, Ramon y Cajal Hospital, Madrid, Spain
| | - C Santiuste
- Department of Infectious Diseases and Biochemistry, Ramon y Cajal Hospital, Madrid, Spain
| | - M J Vivancos
- Department of Infectious Diseases and Biochemistry, Ramon y Cajal Hospital, Madrid, Spain
| | - M Monsalvo
- Department of Infectious Diseases and Biochemistry, Ramon y Cajal Hospital, Madrid, Spain
| | - A Moreno
- Department of Infectious Diseases and Biochemistry, Ramon y Cajal Hospital, Madrid, Spain
| | - M J Perez-Elías
- Department of Infectious Diseases and Biochemistry, Ramon y Cajal Hospital, Madrid, Spain
| | - J M Del Rey
- Department of Infectious Diseases and Biochemistry, Ramon y Cajal Hospital, Madrid, Spain
| | - S Moreno
- Department of Infectious Diseases and Biochemistry, Ramon y Cajal Hospital, Madrid, Spain
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Chazot R, Botelho-Nevers E, Frésard A, Maillard N, Mariat C, Lucht F, Gagneux-Brunon A. Diagnostic challenges of kidney diseases in HIV-infected patients. Expert Rev Anti Infect Ther 2017; 15:903-915. [PMID: 28898114 DOI: 10.1080/14787210.2017.1379395] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
INTRODUCTION Chronic kidney disease (CKD) is a prevalent comorbidity in persons living with HIV infection (PLWH) associated with an increase in cardiovascular morbidity and all-cause mortality. Furthermore, early diagnosis of CKD is difficult in PLWH. Areas covered: We reviewed the main diagnostic tools for CKD in PLWH, and discussed their strengths and limits. We performed a literature search on PubMed to identify reviews and clinical trials dealing with attractive kidney biomarkers of CKD in PLWH, with the following key words: 'HIV AND kidney', 'HIV AND Kidney biomarkers', 'CKD AND Kidney biomarkers'. Expert commentary: Currently, CKD diagnosis is based on the estimation of Glomerular Filtration Rate (GFR), and measurement of proteinuria by urine protein/creatinine ratio (uPCR). These parameters are independent and complementary predictors of outcomes. GFR estimates are lacking in accuracy in PLWH. The best GFR estimate is CKD-EPI study equation. Moreover, low-grade proteinuria is associated with an increased risk of kidney disease progression in PLWH, and guidelines derived from the general population may lack sensitivity. Different biomarkers of kidney diseases like N-acetyl beta glucosaminidase (NAG), Kidney Injury Molecule-1 (KIM-1), and Alpha-1-microglobulin may predict kidney disease progression and mortality in PLWH. Others may help clinicians detect antiretroviral-induced tubulopathy, or predict cardiovascular events. More studies are needed to validate the routine use of these types of biomarkers.
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Affiliation(s)
- Robin Chazot
- a Department of Nephrology, Dialysis, Transplantation and Hypertension , University Hospital of Saint-Étienne , Saint-Étienne , France
| | - Elisabeth Botelho-Nevers
- b Department of Infectious and Tropical Diseases , University Hospital of Saint-Étienne , Saint-Étienne , France.,c GIMAP - Groupe sur l'Immunité des Muqueuses et Agents Pathogènes, EA 3064 , Université Jean Monnet, Université de Lyon , Saint-Étienne , France
| | - Anne Frésard
- b Department of Infectious and Tropical Diseases , University Hospital of Saint-Étienne , Saint-Étienne , France.,c GIMAP - Groupe sur l'Immunité des Muqueuses et Agents Pathogènes, EA 3064 , Université Jean Monnet, Université de Lyon , Saint-Étienne , France
| | - Nicolas Maillard
- a Department of Nephrology, Dialysis, Transplantation and Hypertension , University Hospital of Saint-Étienne , Saint-Étienne , France.,c GIMAP - Groupe sur l'Immunité des Muqueuses et Agents Pathogènes, EA 3064 , Université Jean Monnet, Université de Lyon , Saint-Étienne , France
| | - Christophe Mariat
- a Department of Nephrology, Dialysis, Transplantation and Hypertension , University Hospital of Saint-Étienne , Saint-Étienne , France.,c GIMAP - Groupe sur l'Immunité des Muqueuses et Agents Pathogènes, EA 3064 , Université Jean Monnet, Université de Lyon , Saint-Étienne , France
| | - Frédéric Lucht
- b Department of Infectious and Tropical Diseases , University Hospital of Saint-Étienne , Saint-Étienne , France.,c GIMAP - Groupe sur l'Immunité des Muqueuses et Agents Pathogènes, EA 3064 , Université Jean Monnet, Université de Lyon , Saint-Étienne , France
| | - Amandine Gagneux-Brunon
- b Department of Infectious and Tropical Diseases , University Hospital of Saint-Étienne , Saint-Étienne , France.,c GIMAP - Groupe sur l'Immunité des Muqueuses et Agents Pathogènes, EA 3064 , Université Jean Monnet, Université de Lyon , Saint-Étienne , France
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Bunnell KL, Vibhakar S, Glowacki RC, Gallagher MA, Osei AM, Huhn G. Nephrotoxicity Associated with Concomitant Use of Ledipasvir-Sofosbuvir and Tenofovir in a Patient with Hepatitis C Virus and Human Immunodeficiency Virus Coinfection. Pharmacotherapy 2017; 36:e148-53. [PMID: 27459733 DOI: 10.1002/phar.1803] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Direct-acting antivirals (DAAs) have revolutionized the treatment of hepatitis C virus (HCV) infection, with superior efficacy and safety compared to interferon-based therapies. Despite these improvements, drug interactions with DAAs exist and may be clinically relevant in human immunodeficiency virus (HIV)-coinfected patients. We present a case of nephrotoxicity associated with concomitant use of tenofovir disoproxil fumarate (TDF) and ledipasvir-sofosbuvir (LDV-SOF). A 56-year-old woman with HIV infection who had been taking efavirenz/tenofovir/emtricitabine (EFV/TDF/FTC) for 6 years developed acute kidney injury 8 weeks after initiating LDV-SOF for the treatment of HCV infection. Her serum creatinine concentration peaked at 10 mg/dL, compared with her baseline concentration of 0.9-1 mg/dL. Kidney biopsy revealed acute tubular necrosis and acute interstitial nephritis. Both LDV-SOF and TDF were discontinued, and the patient's serum creatinine concentration decreased to 1.3 mg/dL over the following 6 weeks. We postulate that this adverse drug reaction may have been secondary to the known interaction between ledipasvir and TDF, which results in increased TDF exposure. Despite knowledge of this interaction, LDV-SOF is commonly prescribed in patients with HIV-HCV coinfection, as patients who received LDV-SOF- and TDF-containing regimens in trials have not demonstrated adverse clinical consequences related to this interaction. This case highlights the rare but potentially serious nephrotoxicity that can result from TDF toxicity and serves as a reminder to clinicians to implement close renal function monitoring in patients receiving both LDV-SOF and TDF. Clinicians prescribing LDV-SOF to HCV-HIV-coinfected patients receiving TDF should be cautious about use with concomitant nephrotoxic medications and monitor markers of tubular dysfunction, including urinary phosphorus excretion, and renal injury at baseline and week 4 of therapy. Tenofovir alafenamide and alternative DAAs may also have a role in the management of patients at high risk for renal adverse effects from TDF.
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Affiliation(s)
- Kristen L Bunnell
- College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois
| | - Sonia Vibhakar
- Ruth M. Rothstein CORE Center, Cook Country Health and Hospitals System, Chicago, Illinois.
| | - Robert C Glowacki
- College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois.,John H. Stroger Jr. Hospital, Cook County Health and Hospitals System, Chicago, Illinois
| | - Maureen A Gallagher
- Ruth M. Rothstein CORE Center, Cook Country Health and Hospitals System, Chicago, Illinois
| | - Albert M Osei
- John H. Stroger Jr. Hospital, Cook County Health and Hospitals System, Chicago, Illinois
| | - Gregory Huhn
- Ruth M. Rothstein CORE Center, Cook Country Health and Hospitals System, Chicago, Illinois.,John H. Stroger Jr. Hospital, Cook County Health and Hospitals System, Chicago, Illinois
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Novick TK, Choi MJ, Rosenberg AZ, McMahon BA, Fine D, Atta MG. Tenofovir alafenamide nephrotoxicity in an HIV-positive patient: A case report. Medicine (Baltimore) 2017; 96:e8046. [PMID: 28885375 PMCID: PMC6393094 DOI: 10.1097/md.0000000000008046] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
RATIONALE Tenofovir alafenamide (TAF) is novel prodrug of Tenofovir, a nucleotide reverse transcriptase inhibitor. TAF is less nephrotoxic than its predecessor prodrug, tenofovir disoproxil fumarate (TDF). Tenofovir causes mitochondrial dysfunction and tubular injury when there is elevated accumulation in proximal tubule cells. TAF's unique pharmacokinetic profile enables provision of lower required doses for antiviral efficacy. Lower concentrations reach renal tubules minimizing intracellular accumulation and mitochondrial damage. TAF has not been associated with the histologic markers of tenofovir-associated nephrotoxicity that are seen with TDF, such as dysmorphic mitochondria in proximal tubule cells. Here, we report a patient with dysmorphic mitochondria on kidney biopsy after initiating therapy with TAF. LESSONS This case suggests that at risk individuals may experience tubular mitochondrial injury from lower concentrations of tenofovir with TAF.
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Affiliation(s)
| | | | - Avi Z. Rosenberg
- Department of Pathology, Johns Hopkins University, Baltimore, MD
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Effects of a switch from tenofovir- to abacavir-based antiretroviral therapy, with or without atazanavir, on renal function. J Int AIDS Soc 2016; 19:20995. [PMID: 27624144 PMCID: PMC5022114 DOI: 10.7448/ias.19.1.20995] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2016] [Revised: 07/04/2016] [Accepted: 08/10/2016] [Indexed: 02/04/2023] Open
Abstract
Introduction Tenofovir disoproxil fumarate (TDF)–associated renal dysfunction may abate when TDF is replaced with abacavir (ABC). The extent to which the third drug atazanavir contributes to renal dysfunction is unclear. Methods A retrospective analysis was conducted on adults who had plasma viral load (pVL)<200 copies/mL for≥six months while receiving TDF/lamivudine (3TC) – or TDF/emtricitabine (FTC)–based antiretroviral therapy (ART), then switched to ABC/3TC while retaining the third drug in the ART regimen. CD4, pVL, creatinine, estimated glomerular filtration rate (eGFR), serum phosphorus, urine albumin to creatinine ratio and serum lipids were compared between pre-switch baseline and 3, 6 and 12 months after the switch to ABC. Results A total of 286 patients switched from TDF to ABC between 2004 and 2014: 232 (81%) male, median age 48 years (interquartile range (IQR) 42, 56). The third drug was atazanavir (± ritonavir) in 141 (49%) cases. The pVL was<50 copies/mL in 93 to 96% at all time points. Median serum creatinine was 93 µmol/L (IQR 80–111) at baseline and decreased to 88 µmol/L (IQR 78–98) at 12 months after the switch to ABC. Median eGFR increased from 74 (IQR 60–88) mL/min at baseline to 80 mL/min (IQR 69–89) at 12 months. Results were not significantly different between patients on atazanavir versus those on another third drug. Conclusions Viral suppression was maintained among patients who switched from TDF/3TC or TDF/FTC to ABC/3TC. Serum creatinine and eGFR improved up to 12 months after switching to ABC/3TC, irrespective of whether or not patients were also receiving atazanavir±ritonavir.
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Margot NA, Kitrinos KM, Fordyce M, McCallister S, Miller MD, Callebaut C. Rare emergence of drug resistance in HIV-1 treatment-naïve patients after 48 weeks of treatment with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide. HIV CLINICAL TRIALS 2016; 17:78-87. [PMID: 26892863 DOI: 10.1080/15284336.2016.1142731] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Tenofovir alafenamide (TAF), a novel prodrug of the NtRTI tenofovir (TFV), delivers TFV-diphosphate (TFV-DP) to target cells more efficiently than the current prodrug, tenofovir disoproxil fumarate (TDF), with a 90% reduction in TFV plasma exposure. TAF, within the fixed dose combination of elvitegravir /cobicistat / emtricitabine (FTC)/TAF (E/C/F/TAF), has been evaluated in one Phase 2 and two Phase 3 randomized, double-blinded studies in HIV-infected treatment-naive patients, comparing E/C/F/TAF to E/C/F/TDF. In these studies, the TAF-containing group demonstrated non-inferior efficacy to the TDF-containing comparator group with 91.9% of E/C/F/TAF patients having <50 copies/mL of HIV-1 RNA at week 48. An integrated resistance analysis across these three studies was conducted, including HIV-1 genotypic analysis at screening, and genotypic/phenotypic analysis for patients with HIV-1 RNA>400 copies/mL at virologic failure. Pre-existing primary resistance-associated mutations (RAMs) were observed at screening among the 1903 randomized and treated patients: 7.5% had NRTI-RAMs, 18.2% had NNRTI-RAMs, and 3.4% had primary PI-RAMs. Pre-treatment RAMs did not influence treatment response at Week 48. In the E/C/F/TAF group, resistance development was rare; seven patients (0.7%, 7/978) developed NRTI-RAMs, five of whom (0.5%, 5/978) also developed primary INSTI-RAMs. In the E/C/F/TDF group, resistance development was also rare; seven patients (0.8%, 7/925) developed NRTI-RAMs, four of whom (0.4%, 4/925) also developed primary INSTI-RAMs. An additional analysis by deep sequencing in virologic failures revealed minimal differences compared to population sequencing. Overall, resistance development was rare in E/C/F/TAF-treated patients, and the pattern of emergent mutations was similar to E/C/F/TDF.
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Affiliation(s)
- Nicolas A Margot
- a Gilead Sciences Inc. , 333 Lakeside Drive, Foster City , CA , 94404 , USA
| | - Kathryn M Kitrinos
- a Gilead Sciences Inc. , 333 Lakeside Drive, Foster City , CA , 94404 , USA
| | - Marshall Fordyce
- a Gilead Sciences Inc. , 333 Lakeside Drive, Foster City , CA , 94404 , USA
| | - Scott McCallister
- a Gilead Sciences Inc. , 333 Lakeside Drive, Foster City , CA , 94404 , USA
| | - Michael D Miller
- a Gilead Sciences Inc. , 333 Lakeside Drive, Foster City , CA , 94404 , USA
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Zeder AJ, Hilge R, Schrader S, Bogner JR, Seybold U. Medium-grade tubular proteinuria is common in HIV-positive patients and specifically associated with exposure to tenofovir disoproxil Fumarate. Infection 2016; 44:641-9. [PMID: 27256076 DOI: 10.1007/s15010-016-0911-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Accepted: 05/21/2016] [Indexed: 12/12/2022]
Abstract
OBJECTIVES The aim of this cross-sectional study was to evaluate the prevalence and risk factors of medium-grade proteinuria (100-500 mg/g creatinine) among HIV-positive adults. METHODS Spot urine samples of HIV-positive adults without known renal disease were analyzed quantitatively between January 2009 and February 2011. Demographic and medical data were collected. Multivariate regression models for different patterns of proteinuria were constructed. RESULTS Among 411 patients, 18 (4.4 %) presented albuminuria >300 mg/g creatinine and/or proteinuria >500 mg/g creatinine and were excluded from further analyses. Among the study population of 393 patients, 181 (46.1 %) had no significant proteinuria or albuminuria (<100 and <30 mg/g creatinine, respectively), 60 (15.3 %) had moderate albuminuria, while 152 (38.7 %) had proteinuria without albuminuria, suggesting tubular proteinuria. Independent predictors for medium-grade tubular proteinuria in multivariate analysis were exposure to tenofovir (DF), a CD4 nadir <500/µl, older age, and anti-HCV-antibodies. There was no association with classic renal risk factors like diabetes mellitus and arterial hypertension, or with estimated glomerular filtration rate (eGFR). CONCLUSIONS We detected significant proteinuria in 230 (56.0 %) of 411 HIV-positive patients. Among this group, 152 (66.1 %) had medium-grade proteinuria without albuminuria, which was significantly associated with exposure to tenofovir, older age, a lower CD4 nadir and Hepatitis C. Nephrologic or HIV treatment guidelines fail to detect most of these patients but rather identify patients with high cardiovascular risk. In the absence of an association with eGFR the role of medium-grade tubular proteinuria as a potential early marker of chronic kidney disease remains unclear. Prospective studies are needed.
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Affiliation(s)
- A J Zeder
- Sektion Klinische Infektiologie, Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig-Maximilians-Universität München, Pettenkoferstraße 8a, 80336, Munich, Germany. .,Klinik für Gastroenterologie, Klinikum Dritter Orden München-Nymphenburg, Menzinger Straße 44, 80638, Munich, Germany.
| | - R Hilge
- Klinik für Nephrologie, Klinikum Harlaching, Städtisches Klinikum München, Sanatoriumsplatz 2, 81545, Munich, Germany
| | - S Schrader
- Sektion Klinische Infektiologie, Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig-Maximilians-Universität München, Pettenkoferstraße 8a, 80336, Munich, Germany
| | - J R Bogner
- Sektion Klinische Infektiologie, Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig-Maximilians-Universität München, Pettenkoferstraße 8a, 80336, Munich, Germany
| | - U Seybold
- Sektion Klinische Infektiologie, Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig-Maximilians-Universität München, Pettenkoferstraße 8a, 80336, Munich, Germany
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Mouton JP, Njuguna C, Kramer N, Stewart A, Mehta U, Blockman M, Fortuin-De Smidt M, De Waal R, Parrish AG, Wilson DPK, Igumbor EU, Aynalem G, Dheda M, Maartens G, Cohen K. Adverse Drug Reactions Causing Admission to Medical Wards: A Cross-Sectional Survey at 4 Hospitals in South Africa. Medicine (Baltimore) 2016; 95:e3437. [PMID: 27175644 PMCID: PMC4902486 DOI: 10.1097/md.0000000000003437] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Revised: 03/24/2016] [Accepted: 03/28/2016] [Indexed: 01/11/2023] Open
Abstract
Limited data exist on the burden of serious adverse drug reactions (ADRs) in sub-Saharan Africa, which has high HIV and tuberculosis prevalence. We determined the proportion of adult admissions attributable to ADRs at 4 hospitals in South Africa. We characterized drugs implicated in, risk factors for, and the preventability of ADR-related admissions.We prospectively followed patients admitted to 4 hospitals' medical wards over sequential 30-day periods in 2013 and identified suspected ADRs with the aid of a trigger tool. A multidisciplinary team performed causality, preventability, and severity assessment using published criteria. We categorized an admission as ADR-related if the ADR was the primary reason for admission.There were 1951 admissions involving 1904 patients: median age was 50 years (interquartile range 34-65), 1057 of 1904 (56%) were female, 559 of 1904 (29%) were HIV-infected, and 183 of 1904 (10%) were on antituberculosis therapy (ATT). There were 164 of 1951 (8.4%) ADR-related admissions. After adjustment for age and ATT, ADR-related admission was independently associated (P ≤ 0.02) with female sex (adjusted odds ratio [aOR] 1.51, 95% confidence interval [95% CI] 1.06-2.14), increasing drug count (aOR 1.14 per additional drug, 95% CI 1.09-1.20), increasing comorbidity score (aOR 1.23 per additional point, 95% CI 1.07-1.41), and use of antiretroviral therapy (ART) if HIV-infected (aOR 1.92 compared with HIV-negative/unknown, 95% CI 1.17-3.14). The most common ADRs were renal impairment, hypoglycemia, liver injury, and hemorrhage. Tenofovir disoproxil fumarate, insulin, rifampicin, and warfarin were most commonly implicated, respectively, in these 4 ADRs. ART, ATT, and/or co-trimoxazole were implicated in 56 of 164 (34%) ADR-related admissions. Seventy-three of 164 (45%) ADRs were assessed as preventable.In our survey, approximately 1 in 12 admissions was because of an ADR. The range of ADRs and implicated drugs reflect South Africa's high HIV and tuberculosis burden. Identification and management of these ADRs should be considered in HIV and tuberculosis care and treatment programs and should be emphasized in health care worker training programmes.
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Affiliation(s)
- Johannes P Mouton
- From the Department of Medicine, Division of Clinical Pharmacology, University of Cape Town, Cape Town (JPM, CN, NK, AS, UM, MB, MFDS, RDW, GM, KC); Department of Medicine, East London Hospital Complex and Walter Sisulu University, East London (AGP); Department of Medicine, Edendale Hospital, Pietermaritzburg, South Africa (DPKW), US Centers for Disease Control and Prevention, Pretoria (EUI, GA); National Department of Health, Pretoria (MD); and Pharmaceutical Services, School of Health Sciences, University of KwaZulu-Natal, Durban, South Africa (MD)
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Piratvisuth T, Komolmit P, Chan HL, Tanwandee T, Sukeepaisarnjaroen W, Pessoa MG, Fassio E, Ono SK, Bessone F, Daruich J, Zeuzem S, Manns M, Uddin A, Dong Y, Trylesinski A. Efficacy of telbivudine with conditional tenofovir intensification in patients with chronic hepatitis B: results from the 2-year roadmap strategy. Drugs Context 2016; 5:212294. [PMID: 27403192 PMCID: PMC4924977 DOI: 10.7573/dic.212294] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Indexed: 12/15/2022] Open
Abstract
Background: A 2-year roadmap study was conducted to evaluate the efficacy and safety of tenofovir intensification at Week 24 in patients with chronic hepatitis B (CHB) receiving telbivudine. Scope: A prospective multicenter study was conducted in treatment-naive patients with hepatitis B e antigen (HBeAg)-positive CHB. All patients received telbivudine (600 mg/day) until Week 24. Thereafter, patients with detectable hepatitis B virus (HBV) DNA (≥300 copies/mL) were administered tenofovir (300 mg/day) plus telbivudine, and patients with undetectable HBV DNA continued telbivudine monotherapy until Week 104. The primary endpoint was the proportion of patients with undetectable HBV DNA (<300 copies/mL) at Weeks 52 and 104. Findings: A total of 105 patients were enrolled in the trial, of which 100 were eligible for efficacy analysis. Undetectable HBV DNA levels were observed at Week 24 in 55 patients who continued on with telbivudine monotherapy. The remaining 45 patients with detectable HBV DNA received tenofovir add-on therapy. With monotherapy, 100% (55/55) and 94.5% (52/55) of patients achieved HBV DNA <300 copies/mL at Weeks 52 and 104, respectively; the corresponding values for patients with add-on therapy were 84.4% (38/45) and 93.3% (42/45). Overall, undetectable HBV DNA (<300 copies/mL) was found in 93% (93/100) and 94% (94/100) of patients at Weeks 52 and 104, respectively. HBeAg seroconversion rate was 44.4% (44/99) at Week 104 for the overall patient population. One patient in the monotherapy group and six in the intensification group demonstrated HBsAg clearance at Week 104. HBsAg seroconversion was observed in four patients at Week 104, all belonged to the tenofovir intensification group. Eight patients sustained HBsAg loss during a posttreatment follow-up period of 16 weeks. Alanine aminotransferase (ALT) normalization was constant in the telbivudine monotherapy group, whereas a progressive improvement was observed in the tenofovir intensification group. Two patients in the monotherapy and none in the intensification group experienced viral breakthrough by Week 104. There were no reports of myopathy in either group. The mean changes in estimated glomerular filtration rate (eGFR), estimated using the Modification of Diet in Renal Disease (MDRD) formula, from baseline to Week 104 were +6.145 mL/min/1.73 m2 (p=0.0230) and +7.954 mL/min/1.73 m2 (p=0.0154) in the telbivudine monotherapy and tenofovir intensification groups, respectively. The incidence of serious AEs was four in the telbivudine monotherapy and two in the tenofovir intensification group. The main limitation of this study was limited sample size, which made the power of the observation low, and the absence of a comparative subgroup to assess the progression of patients with detectable HBV DNA without treatment intensification. Conclusions: Data from this 2-year roadmap study confirmed that telbivudine with add-on tenofovir was effective and well tolerated in patients with CHB. Telbivudine was associated with an improvement in eGFR from baseline in both the groups.
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Affiliation(s)
- Teerha Piratvisuth
- NKC Institute of Gastroenterology and Hepatology, Songklanagarind Hospital, Faculty of Medicine, Prince of Songkla University, Hat Yai, Thailand
| | - Piyawat Komolmit
- Division of Gastroenterology, Department of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Henry Ly Chan
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong S.A.R, China
| | | | | | - Mário G Pessoa
- Division of Gastroenterology and Hepatology, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Eduardo Fassio
- Hospital Nacional Prof. Alejandro Posadas, Buenos Aires, Argentina
| | - Suzane K Ono
- Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo, Brazil
| | | | - Jorge Daruich
- Hospital de Clínicas San Martín, University of Buenos Aires, Buenos Aires, Argentina
| | - Stefan Zeuzem
- Department of Medicine, JW Goethe University Hospital, Theodor-Stern-Kai 7, Frankfurt a.M., Germany
| | - Michael Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Alkaz Uddin
- Novartis Pharmaceutical Corporation, East Hanover, NJ, USA
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Bonora S, Calcagno A, Trentalange A, Di Perri G. Elvitegravir, cobicistat, emtricitabine and tenofovir alafenamide for the treatment of HIV in adults. Expert Opin Pharmacother 2016; 17:409-19. [DOI: 10.1517/14656566.2016.1129401] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
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Thu AM, Poovorawan K, Kittitrakul C, Nontprasert A, Sriboonvorakul N, Phumratanaprapin W, Tangkijvanich P, Leowattana W, Wilairatana P. Nephrotoxicity caused by oral antiviral agents in patients with chronic hepatitis B treated in a hospital for tropical diseases in Thailand. BMC Pharmacol Toxicol 2015; 16:38. [PMID: 26651337 PMCID: PMC4677430 DOI: 10.1186/s40360-015-0037-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Accepted: 11/18/2015] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND There is increasing concern about the potential for nephrotoxicity in patients with chronic hepatitis B (CHB) treated long-term with nucleotide analogs. METHODS We examined renal dysfunction and its associated risk factors in patients with CHB treated with antiviral regimens containing either nucleosides or nucleotide analogs. We undertook a retrospective cohort study from 2006 to 2014 at the Hospital for Tropical Diseases, Bangkok, Thailand, and analyzed the data of 102 patients with a median follow-up time of 44.5 months (range 4-101 months). RESULTS Seventy-three patients were treated with an antiviral regime containing a nucleoside analog, and 29 with a regime containing a nucleotide analog. Abnormally elevated serum creatinine concentration was observed in 12 patients (11.8 %) after 8 years of treatment. Thirty one percent of patients treated with nucleotide analogs had elevated serum creatinine levels and three of these patients (10.3 %) developed nephrotoxicity. In contrast, serum creatinine concentrations were elevated in three of the 73 patients treated with a nucleoside analog (4.1 %), and none developed nephrotoxicity. The incidence of renal dysfunction by the nucleotide analog regimen was cumulative, with 11.1, 21.0, 26.5 and 47.6 % of patients affected after 2, 4, 6 and 8 years, respectively. Univariate and multivariate analysis indicated that a nucleotide analog-based regimen significantly predicted renal dysfunction (odds ratio 10.5, 95 % confidence intervals 2.6-42.4, P <0.001). CONCLUSION The long-term use of nucleotide analogs increased the risk of nephrotoxicity in patients with CHB. Thus, the regular assessment of renal function is recommended for all patients with CHB, particularly those treated with a nucleotide analog.
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Affiliation(s)
- Aung Myint Thu
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
| | - Kittiyod Poovorawan
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
| | - Chatporn Kittitrakul
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
| | - Apichart Nontprasert
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
| | - Natthida Sriboonvorakul
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
| | - Weerapong Phumratanaprapin
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
| | - Pisit Tangkijvanich
- Research Unit of Hepatitis and Liver Cancer, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
| | - Wattana Leowattana
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
| | - Polrat Wilairatana
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
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Hwang HS, Park CW, Song MJ. Tenofovir-associated Fanconi syndrome and nephrotic syndrome in a patient with chronic hepatitis B monoinfection. Hepatology 2015; 62:1318-1320. [PMID: 25645518 DOI: 10.1002/hep.27730] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2014] [Accepted: 01/20/2015] [Indexed: 12/26/2022]
Abstract
Tenofovir disoproxil fumarate (TDF) is widely used as an effective first-line therapy for chronic hepatitis B (CHB) infection. While TDF demonstrates successful viral suppression, it has been linked to the development of renal proximal tubular (PT) dysfunction, leading to Fanconi syndrome. However, Fanconi syndrome has been rarely reported in CHB-monoinfected patients, and there were no reports of TDF-associated nephrotic syndrome. Here, we report a case of combined Fanconi and nephrotic syndrome in CHB patients after TDF exposure.
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Affiliation(s)
- Hyeon Seok Hwang
- Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Cheol Whee Park
- Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Myeong Jun Song
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
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Ahlström MG, Feldt-Rasmussen B, Legarth R, Kronborg G, Pedersen C, Larsen CS, Gerstoft J, Obel N. Smoking and renal function in people living with human immunodeficiency virus: a Danish nationwide cohort study. Clin Epidemiol 2015; 7:391-9. [PMID: 26357490 PMCID: PMC4559253 DOI: 10.2147/clep.s83530] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
INTRODUCTION Smoking is a main risk factor for morbidity and mortality in people living with human immunodeficiency virus (PLHIV), but its potential association with renal impairment remains to be established. METHODS We did a nationwide population-based cohort study in Danish PLHIV to evaluate the association between smoking status and 1) overall renal function and risk of chronic kidney disease (CKD), 2) risk of any renal replacement therapy (aRRT), and 3) mortality following aRRT. We calculated estimated creatinine clearance using the Cockcroft-Gault equation (CG-CrCl), and evaluated renal function graphically. We calculated cumulative incidence of CKD (defined as two consecutive CG-CrCls of ≤60 mL/min, ≥3 months apart) and aRRT and used Cox regression models to calculate incidence rate ratios (IRRs) for risk of CKD, aRRT, and mortality rate ratios (MRRs) following aRRT. RESULTS From the Danish HIV Cohort Study, we identified 1,475 never smokers, 768 previous smokers, and 2,272 current smokers. During study period, we observed no association of smoking status with overall renal function. Previous and current smoking was not associated with increased risk of CKD (adjusted IRR: 1.1, 95% confidence interval [CI]: 0.7-1.7; adjusted IRR: 1.3, 95% CI: 0.9-1.8) or aRRT (adjusted IRR: 0.8, 95% CI: 0.4-1.7; adjusted IRR: 0.9, 95% CI: 0.5-1.7). Mortality following aRRT was high in PLHIV and increased in smokers vs never smokers (adjusted MRR: 3.8, 95% CI: 1.3-11.2). CONCLUSION In Danish PLHIV, we observed no strong association between smoking status and renal function, risk of CKD, or risk of aRRT, but mortality was increased in smokers following aRRT.
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Affiliation(s)
- Magnus Glindvad Ahlström
- Department of Infectious Diseases, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Bo Feldt-Rasmussen
- Department of Nephrology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Rebecca Legarth
- Department of Infectious Diseases, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Gitte Kronborg
- Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, Denmark
| | - Court Pedersen
- Department of Infectious Diseases, Odense University Hospital, Odense, Denmark
| | - Carsten Schade Larsen
- Department of Infectious Diseases, Aarhus University Hospital, Skejby, Aarhus, Denmark
| | - Jan Gerstoft
- Department of Infectious Diseases, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Niels Obel
- Department of Infectious Diseases, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
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The case of chronic hepatitis B treatment with tenofovir: an update for nephrologists. J Nephrol 2015; 28:393-402. [DOI: 10.1007/s40620-015-0214-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2015] [Accepted: 05/22/2015] [Indexed: 12/29/2022]
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Quesada PR, Esteban LL, García JR, Sánchez RV, García TM, Alonso-Vega GG, Ferrández JSR. Incidence and risk factors for tenofovir-associated renal toxicity in HIV-infected patients. Int J Clin Pharm 2015; 37:865-72. [PMID: 26008219 DOI: 10.1007/s11096-015-0132-1] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2014] [Accepted: 05/06/2015] [Indexed: 01/11/2023]
Abstract
BACKGROUND Since the beginning of highly active antiretroviral therapy utilization, the association of renal impairment with treatment toxicity is more prevalent. Tenofovir disoproxil fumarate (TDF) side effects include renal toxicity. OBJECTIVE To assess the incidence of renal damage in human immunodeficiency virus (HIV)-positive patients treated with TDF and to identify associated potential risk factors. SETTING A public university tertiary 450-beds hospital in Spain. METHOD Retrospective, longitudinal observational study that included adult HIV-1-infected patients treated with TDF. Patient´s treated with TDF from January 2010 to December 2012 were included. Patient follow-up started when initiating treatment with TDF up until either end of treatment or end of study (July 31, 2013). The estimated glomerular filtration rate was calculated using the four-variable modification of diet in renal disease. Renal toxicity was classified as moderate [estimated glomerular filtration rate (eGFR) < 60 ml/min] or severe (eGFR < 30 ml/min). The incidence rate for moderate and severe renal insufficiency was calculated as number of cases per 1000 patient-year. A univariate analysis and binary logistic regression was carried out in order to identify risk factors associated with renal toxicity by using the forward stepwise method (likelihood ratio) MAIN OUTCOME MEASURE Incidence rate for moderate and severe renal insufficiency (RI) RESULTS: 451 patients were included in the study. The incidence rate of moderate RI was 29.2 cases per 1000 person-year (95% CI 22.1-36.3), whereas the incidence of severe RI was 2.2 cases per 1000 person-year (95% CI 0.3-4.1). Multivariate analysis confirmed an independent association with the risk of kidney damage for age (OR 1.08 95% CI 1.05-1.12), time on treatment with TDF (OR 1.16 95% CI 1.04-1.30), baseline creatinine (OR 49.80 95% CI 7.90-311.92) and treatment with NNRTIs (OR 0.45 95% CI 0.24-0.83). CONCLUSION Mild to moderate renal failure is a frequent complication during treatment with TDF although severe renal impairment is scarce. Risk factors include age, duration of treatment with TDF, elevated baseline creatinine levels, and treatment with protease inhibitor boosted with ritonavir combinations.
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A LC-MS method to quantify tenofovir urinary concentrations in treated patients. J Pharm Biomed Anal 2015; 114:8-11. [PMID: 25997174 DOI: 10.1016/j.jpba.2015.05.001] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2015] [Revised: 04/24/2015] [Accepted: 05/01/2015] [Indexed: 11/21/2022]
Abstract
Tenofovir disoproxil fumarate is a prodrug of tenofovir used in the treatment of HIV and HBV infections: it is the most used antiretroviral worldwide. Tenofovir is nucleotidic HIV reverse trascriptase inhibitor that showed excellent long-term efficacy and tolerability. However renal and bone complications (proximal tubulopathy, hypophosphatemia, decreased bone mineral density, and reduced creatinine clearance) limit its use. Tenofovir renal toxicity has been suggested as the consequence of drug entrapment in proximal tubular cells: measuring tenofovir urinary concentrations may be a proxy of this event and it may be used as predictor of tenofovir side effects. No method is currently available for quantifying tenofovir in this matrix: then, the aim of this work was to validate a new LC-MS method for the quantification of urinary tenofovir. Chromatographic separation was achieved with a gradient (acetonitrile and water with formic acid 0.05%) on an Atlantis 5 μm T3, 4.6 mm × 150 mm, reversed phase analytical column. Detection of tenofovir and internal standard was achieved by electrospray ionization mass spectrometry in the positive ion mode. Calibration ranged from 391 to 100,000 ng/mL. The limit of quantification was 391 ng/mL and the limit of detection was 195 ng/mL. Mean recovery of tenofovir and internal standard were consistent and stable, while matrix effect resulted low and stable. The method was tested on 35 urine samples from HIV-positive patients treated with tenofovir-based HAARTs and did not show any significant interference with antiretrovirals or other concomitantly administered drugs. All the observed concentrations in real samples fitted the calibration range, confirming the capability of this method for the use in clinical routine. Whether confirmed in ad hoc studies this method may be used for quantifying tenofovir urinary concentrations and help managing HIV-positive patients treated with tenofovir.
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Efficacy, safety and pharmacokinetics of tenofovir disoproxil fumarate in virologic-suppressed HIV-infected children using weight-band dosing. Pediatr Infect Dis J 2015; 34:392-7. [PMID: 25760566 DOI: 10.1097/inf.0000000000000633] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Tenofovir disoproxil fumarate (TDF) is approved for children but concerns remain about long-term renal and bone toxicity. We evaluated the efficacy, safety and pharmacokinetics of TDF in treatment-experienced children during 96 weeks. METHODS This was a prospective, open-label study in HIV-infected children 3-18 years of age (≥15 kg), with viral suppression on their first-line regimen without tenofovir. Children were given TDF/lamivudine/efavirenz once daily at entry; TDF was prescribed according to weight bands. Age-, gender- and CD4-matched controls receiving TDF-sparing regimens were concomitantly enrolled. Tenofovir pharmacokinetic assessment was performed at week 4. CD4 counts, HIV-1 RNA viral load and safety assessments were determined at baseline, 24, 48 and 96 weeks. RESULTS Eighty children were enrolled (40 per group); 35 (44%) were male. Median age was 12.2 (range 3.1-17.7) years. The median administered dose was 214 mg/m. Tenofovir geometric mean AUC0-24 hours, Cmax and C24 hours were 2.66 [90% confidence interval (CI) 2.49-2.84] μg hours/mL, 0.26 (0.24-0.29) μg/mL and 0.057 (0.052-0.062) μg/mL, respectively. Estimated glomerular filtration rate did not significantly change overtime. The fractional excretion of calcium slightly increased but fractional excretion of phosphate was unchanged among children in TDF group. The bone mineral density Z score decreased in the first 24 weeks of TDF treatment and was stable afterward. The TDF group had lower cholesterol levels (P = 0.001). Thirty-nine of 40 children remained virologically suppressed. No serious adverse event related to tenofovir. CONCLUSION TDF substitution in children and adolescents who were otherwise stable while receiving a first-line nonnucleoside reverse transcriptase inhibitor-based regimen achieved adequate exposure without clinically significant renal or bone adverse events over 96 weeks. While reassuring, these preliminary safety findings may not exclude delayed effects on renal function and bone density.
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Lê MP, Landman R, Koulla-Shiro S, Charpentier C, Sow PS, Diallo MB, Ngom Gueye NF, Ngolle M, Le Moing V, Eymard-Duvernay S, Benalycherif A, Delaporte E, Girard PM, Peytavin G. Tenofovir plasma concentrations related to estimated glomerular filtration rate changes in first-line regimens in African HIV-infected patients: ANRS 12115 DAYANA substudy. J Antimicrob Chemother 2015; 70:1517-21. [PMID: 25583749 DOI: 10.1093/jac/dku532] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2014] [Accepted: 12/01/2014] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVES An open-label randomized trial (DAYANA) was conducted in sub-Saharan settings to evaluate four different regimens containing tenofovir disoproxil fumarate as first-line treatment for HIV infection. The objectives of the present substudy were to assess the relationship between trough concentrations of tenofovir in plasma collected after 24 h (C24) and estimated glomerular filtration rates (eGFR) calculated by the different formulae that are available. METHODS The criteria for eligibility were those of the DAYANA trial, recruiting naive patients. The four tenofovir regimens were: Group 1, tenofovir/emtricitabine/nevirapine; Group 2, tenofovir/lopinavir/ritonavir; Group 3, tenofovir/emtricitabine/zidovudine; and Group 4, tenofovir/emtricitabine/efavirenz. The C24 of tenofovir was determined using LC-MS/MS. The eGFR was calculated using the Cockcroft-Gault, Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formulae. RESULTS The median C24 of tenofovir was 42 ng/mL. The C24 of tenofovir was higher with lopinavir/ritonavir than with the other three regimens: at Week 4, 84 ng/mL versus 25 ng/mL; and at Week 48, 81 ng/mL versus 52 ng/mL. The baseline merged eGFR was 98.2 mL/min/1.73 m(2) with the CKD-EPI equation. Only the mean changes in eGFR in Group 2 differed from the absolute value of zero (-8.2 mL/min/1.73 m(2)) with the CKD-EPI equation between baseline and Week 48. The Cockcroft-Gault formula is inappropriate for these African patients because it underestimated the baseline eGFR and overestimated the changes in eGFR between baseline and Week 48. CONCLUSIONS In this population of mostly female HIV-1-infected African patients, tenofovir plasma overexposure was associated with PI/ritonavir and a time-dependent decrease in eGFR, probably via an inhibition of MRP2/MRP4 efflux transporters. The close monitoring over time of the eGFR using MDRD or CKD-EPI calculations and by using other biomarkers of renal disorder should be proposed as an alternative to therapeutic drug monitoring in resource-limited countries.
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Affiliation(s)
- Minh Patrick Lê
- APHP, Bichat-Claude Bernard Hospital, Clinical Pharmaco-Toxicology Department, Paris, France
| | - Roland Landman
- Institut de Médecine et d'Epidémiologie Appliquée, Paris, France APHP, Bichat-Claude Bernard Hospital, Tropical and Infectious Disease Department, Paris, France IAME, UMR 1137, Univ Paris Diderot, Sorbonne Paris Cité, and INSERM, Paris, France
| | | | - Charlotte Charpentier
- IAME, UMR 1137, Univ Paris Diderot, Sorbonne Paris Cité, and INSERM, Paris, France APHP, Bichat-Claude Bernard Hospital, Virology Department, Paris, France
| | | | | | | | | | - Vincent Le Moing
- Department of Infectious Diseases, CHU Montpellier, Montpellier, France
| | - Sabrina Eymard-Duvernay
- UMI 233, Institut de Recherche pour le Développement-Université Montpellier 1, Montpellier, France
| | | | - Eric Delaporte
- Department of Infectious Diseases, CHU Montpellier, Montpellier, France UMI 233, Institut de Recherche pour le Développement-Université Montpellier 1, Montpellier, France
| | - Pierre-Marie Girard
- Institut de Médecine et d'Epidémiologie Appliquée, Paris, France APHP, Saint-Antoine Hospital, Department of Infectious Diseases, Pierre et Marie Curie University, Paris, France
| | - Gilles Peytavin
- APHP, Bichat-Claude Bernard Hospital, Clinical Pharmaco-Toxicology Department, Paris, France IAME, UMR 1137, Univ Paris Diderot, Sorbonne Paris Cité, and INSERM, Paris, France
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Mandala J, Nanda K, Wang M, De Baetselier I, Deese J, Lombaard J, Owino F, Malahleha M, Manongi R, Taylor D, Van Damme L. Liver and renal safety of tenofovir disoproxil fumarate in combination with emtricitabine among African women in a pre-exposure prophylaxis trial. BMC Pharmacol Toxicol 2014; 15:77. [PMID: 25539648 PMCID: PMC4297367 DOI: 10.1186/2050-6511-15-77] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2014] [Accepted: 12/08/2014] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND Safety of tenofovir disoproxil fumarate/emtricitabine (TDF-FTC) has been studied more extensively among HIV-infected patients than among HIV-uninfected people. Using data from a pre-exposure trial - FEM-PrEP -, we determined the cumulative probabilities of grade 1+ ALT, AST and creatinine and grade 2+ phosphorus toxicities; ALT/AST toxicities by baseline hepatitis B status; and change in mean creatinine, phosphorus, ALT and AST levels controlling for TDF-FTC adherence. METHODS AND FINDINGS FEM-PrEP was a randomized, blinded, placebo-controlled trial of daily TDF-FTC among women in Africa. Enrolled women were in general good health, HIV antibody negative, 18 to 35 years old, hepatitis B surface antigen negative, and had normal hepatic and renal function at baseline. AST, ALT, phosphorus and serum creatinine were measured regularly throughout the trial. TDF-FTC concentrations were measured to assess adherence to TDF-FTC. The cumulative probabilities of grade 1+ creatininemia and grade 2+ phosphatemia toxicities were not statistically different between TDF-FTC and placebo arms. The cumulative probabilities of grade 1+ ALT and AST toxicities were higher among participants in the TDF-FTC arm than in the placebo arm (p = 0.03 for both). The proportions of grade 1+ and grade 2+ ALT or AST toxicities were significantly higher in participants who were hepatitis B virus surface antibody (HBsAb) positive than in those who were HBsAb-negative. Women with good adherence had higher mean change from baseline to week 4 in their AST levels (2.90 (0.37, 5.42); p = 0.025) than women with less than good adherence. CONCLUSIONS We did not observe a significant relationship between randomization to TDF-FTC and creatinine or phosphorus toxicities. Women randomized to TDF-FTC had higher rates of mild to moderate ALT/AST toxicities, especially women with prior hepatitis B virus exposure. We also observed a significant increase in AST from baseline to week 4 among women who had higher adherence to TDF-FTC during that interval. TRIAL REGISTER #NCT00625404, February 19, 2008.
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Affiliation(s)
- Justin Mandala
- FHI 360, 1825 Connecticut Ave, Suite 800, NW, Washington, DC 20009, USA.
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Moss DM, Neary M, Owen A. The role of drug transporters in the kidney: lessons from tenofovir. Front Pharmacol 2014; 5:248. [PMID: 25426075 PMCID: PMC4227492 DOI: 10.3389/fphar.2014.00248] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2014] [Accepted: 10/24/2014] [Indexed: 12/15/2022] Open
Abstract
Tenofovir disoproxil fumarate, the prodrug of nucleotide reverse transcriptase inhibitor tenofovir, shows high efficacy and relatively low toxicity in HIV patients. However, long-term kidney toxicity is now acknowledged as a modest but significant risk for tenofovir-containing regimens, and continuous use of tenofovir in HIV therapy is currently under question by practitioners and researchers. Co-morbidities (hepatitis C, diabetes), low body weight, older age, concomitant administration of potentially nephrotoxic drugs, low CD4 count, and duration of therapy are all risk factors associated with tenofovir-associated tubular dysfunction. Tenofovir is predominantly eliminated via the proximal tubules of the kidney, therefore drug transporters expressed in renal proximal tubule cells are believed to influence tenofovir plasma concentration and toxicity in the kidney. We review here the current evidence that the actions, pharmacogenetics, and drug interactions of drug transporters are relevant factors for tenofovir-associated tubular dysfunction. The use of creatinine and novel biomarkers for kidney damage, and the role that drug transporters play in biomarker disposition, are discussed. The lessons learnt from investigating the role of transporters in tenofovir kidney elimination and toxicity can be utilized for future drug development and clinical management programs.
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Affiliation(s)
- Darren M Moss
- Department of Molecular and Clinical Pharmacology, University of Liverpool Liverpool, UK
| | - Megan Neary
- Department of Molecular and Clinical Pharmacology, University of Liverpool Liverpool, UK
| | - Andrew Owen
- Department of Molecular and Clinical Pharmacology, University of Liverpool Liverpool, UK
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49
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Touzard Romo F, Smeaton LM, Campbell TB, Riviere C, Mngqibisa R, Nyirenda M, Supparatpinyo K, Kumarasamy N, Hakim JG, Flanigan TP. Renal and metabolic toxicities following initiation of HIV-1 treatment regimen in a diverse, multinational setting: a focused safety analysis of ACTG PEARLS (A5175). HIV CLINICAL TRIALS 2014; 15:246-60. [PMID: 25433664 PMCID: PMC4357257 DOI: 10.1310/hct1506-246] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
BACKGROUND Convenient dosing, potency, and low toxicity support use of tenofovir disoproxil fumarate (TDF) as preferred nucleotide reverse transcriptase inhibitor (NRTI) for HIV-1 treatment. However, renal and metabolic safety of TDF compared to other NRTIs has not been well described in resource-limited settings. METHODS This was a secondary analysis examining the occurrence of renal abnormalities (RAs) and renal and metabolic serious non-AIDS-defining events (SNADEs) through study follow-up between participants randomized to zidovudine (ZDV)/lamivudine/ efavirenz and TDF/emtricitabine/efavirenz treatment arms within A5175/PEARLS trial. Exact logistic regression explored associations between baseline covariates and RAs. Response profile longitudinal analysis compared creatinine clearance (CrCl) over time between NRTI groups. RESULTS Twenty-one of 1,045 participants developed RAs through 192 weeks follow-up; there were 15 out of 21 in the TDF arm (P = .08). Age 41 years or older (odds ratio [OR], 3.35; 95% CI, 1.1-13.1), his- tory of diabetes (OR, 10.7; 95% CI, 2.1-55), and lower baseline CrCl (OR, 3.1 per 25 mL/min decline; 95% CI, 1.7-5.8) were associated with development of RAs. Renal SNADEs occurred in 42 participants; 33 were urinary tract infections and 4 were renal failure/insufficiency; one event was attributed to TDF. Significantly lower CrCl values were maintained among patients receiving TDF compared to ZDV (repeated measures analysis, P = .05), however worsening CrCl from baseline was not observed with TDF exposure over time. Metabolic SNADEs were rare, but were higher in the ZDV arm (20 vs 3; P < .001). CONCLUSIONS TDF is associated with lower serious metabolic toxicities but not higher risk of RAs, serious renal events, or worsening CrCl over time compared to ZDV in this randomized multinational study.
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Affiliation(s)
- F Touzard Romo
- The Miriam Hospital, Providence, Rhode Island, USA Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA
| | - L M Smeaton
- Harvard School of Public Health, Boston, Massachusetts, USA
| | - T B Campbell
- University of Colorado Denver, Aurora, Colorado, USA
| | - C Riviere
- Institut Nacional de Laboratoire et Recherches, Port-au-Prince, Haiti
| | - R Mngqibisa
- University of KwaZulu-Natal, Durban, South Africa
| | - M Nyirenda
- College of Medicine - Johns Hopkins Research Project, Blantyre, Malawi
| | | | - N Kumarasamy
- YRG Centre for AIDS Research and Education, Chennai, India
| | - J G Hakim
- University of Zimbabwe College of Health Sciences, Harare, Zimbabwe
| | - T P Flanigan
- The Miriam Hospital, Providence, Rhode Island, USA Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA
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50
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Mausumee G, Frank S, Shawn C, Dara H, Zhao Y, Soleil PM, Sanderson TP, Michael G, Marc D. Nonclinical Safety Profile of BMS-986001, a Nucleoside Transcriptase Inhibitor for Combination Retroviral Therapy. Int J Toxicol 2014; 33:204-218. [PMID: 24846376 DOI: 10.1177/1091581814529309] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Nucleoside reverse transcriptase inhibitors (NRTIs)/nucleotide reverse transcriptase inhibitors are key components of combination antiretroviral therapy for HIV infection. First-generation NRTIs are associated with mitochondrial toxicity in patients, mainly due to inhibition of human DNA polymerase γ (hDNA polγ) that manifests as adverse events such as lipodystrophy, lactic acidosis, myopathy, cardiomyopathy, or nephropathy in patients. In chronic nonclinical studies in rodents and nonrodents, eukaryotic (host) mitochondrial toxicity manifests as some drug-specific toxicities similar to human toxicity. BMS-986001, a novel thymidine analog with minimal hDNA polγ inhibition, has demonstrated antiretroviral activity in early clinical studies. The primary toxicity of BMS-986001 in rats and monkeys is bone marrow dyserythropoiesis with associated decreases in red blood cell mass. Additionally, at high doses, severe platelet reductions accompanied by cutaneous petechiae began during weeks 8 and 11 in 3 of 60 monkeys in chronic toxicity studies. In a 6-month study, platelet reductions required euthanasia of the 2 affected monkeys (300 mg/kg/d) at week 14, but with dose reduction (200 mg/kg/d) remaining monkeys had no platelet changes. One affected monkey (200 mg/kg/d) in a 9-month study completed dosing and its platelet counts recovered during a 1-month recovery. Formation of platelet-bound immunoglobulin in the presence of BMS-986001, together with rapid and complete platelet recovery in the absence of BMS-986001, suggested that platelet decreases in monkeys may be immune mediated. No findings indicative of mitochondrial toxicity were observed in rats or monkeys given BMS-986001, suggesting an improved safety profile compared to marketed NRTI or tenofovir disoproxil fumarate.
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Affiliation(s)
- Guha Mausumee
- Research and Development, Bristol-Myers Squibb Company, Mt Vernon, IN, USA
| | - Simutis Frank
- Research and Development, Bristol-Myers Squibb Company, Mt Vernon, IN, USA
| | - Clark Shawn
- Research and Development, Bristol-Myers Squibb Company, Mt Vernon, IN, USA
| | - Hawthorne Dara
- Research and Development, Bristol-Myers Squibb Company Lawrenceville, NJ, USA
| | - Yue Zhao
- Research and Development, Bristol-Myers Squibb Company Lawrenceville, NJ, USA
| | | | - Thomas P Sanderson
- Research and Development, Bristol-Myers Squibb Company, Mt Vernon, IN, USA
| | - Graziano Michael
- Research and Development, Bristol-Myers Squibb Company Lawrenceville, NJ, USA
| | - Davies Marc
- Research and Development, Bristol-Myers Squibb Company Lawrenceville, NJ, USA
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